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The ONLY Legit Ways to Lose Fat While Sleeping (the rest is BS)Increase thermogenic potential -
They also thought this fat disappeared by the time most people reached adulthood. Researchers now know that even adults have small reserves of brown fat. This recruitable type is found in muscles and white fat throughout your body.
Certain drugs can cause the browning of white fat. Thiazolidinediones TZDs , a type of drug used to help manage insulin resistance, can help with brown fat accumulation.
But TZD medications are prescribed to people diagnosed with diabetes and are not available to others. TZDs are also associated with weight gain, fluid retention, and other side effects. Exposing your body to cool and even cold temperatures may help recruit more brown fat cells.
Some research suggests that just 2 hours of exposure each day to temperatures around 66°F 19°C may be enough to turn recruitable fat brown. You may consider taking a cold shower or ice bath.
Turning the thermostat down a few degrees in your home or going outside in cold weather are other ways to cool your body and possibly create more brown fat. Other research on mice suggests that a protein called irisin may help transform white fat to brown.
Humans also produce this protein. One study found that people who were more sedentary produced less irisin than those who exercised more often. Specifically, levels are increased when people do more intense aerobic interval training. Exercise is highly recommended by doctors for heart health and weight management.
Current physical activity guidelines for adults include doing one of the following every week:. But exercise still has many health benefits. More research is needed on humans. Researchers are still trying to understand the genes that control how white and brown fat develops.
In one study , scientists engineered mice to be born with very little brown fat by limiting a protein called Type 1A BMP-receptor. When exposed to cold, the mice created brown fat from their white fat and muscles anyway, showing the power of recruitment.
Researchers have also discovered that a certain protein called early B-cell factor-2 Ebf2 might play a key role in building brown fat. When engineered mice had exposure to high levels of Ebf2, it transformed white fat to brown fat.
These cells consumed more oxygen, which shows that the brown fat was indeed producing heat and burning calories. A review on various studies has shown that brown fat burns calories and may help control blood sugar and improve insulin levels, decreasing the risk for type 2 diabetes.
It may also help with removing fats from the blood, decreasing the risk for hyperlipidemia. More research is needed before doctors can hand out a pill or other quick fix to convert white fat to brown. Before you start taking ice baths, eating more, or turning down your thermostat, start by making small changes to your diet and trying some low impact exercises.
Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. VIEW ALL HISTORY. Some fats are better for you than others and may even promote good heart health.
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Check out these simple ways to lower your…. A Quiz for Teens Are You a Workaholic? The most common complaints include nausea , constipation, abdominal pain and headache. Supplements containing mg or more of caffeine may cause heart palpitations, anxiety, headache, restlessness and dizziness Several studies have reported a link between these types of supplements and severe inflammation of the intestinal tract — sometimes hazardous enough to require surgery 37 , Others have reported episodes of hepatitis inflammation of the liver , liver damage and even liver failure in otherwise healthy teens and adults 39 , 40 , 41 , Always examine ingredients and speak with your healthcare provider before deciding whether thermogenic supplements are right for you.
The most common side effects of thermogenic supplements are minor. However, some people experience serious complications, such as inflammatory bowel disease or liver failure.
Always use caution and speak to your doctor before taking a new supplement. They may be more effective when paired with other diet and exercise changes but are not a magic pill solution.
Always speak with your doctor before trying a new supplement, since some people have experienced serious complications. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.
There are several effective supplements that can help you burn body fat. This article lists 5 natural fat burners that are supported by science. Caffeine is a natural stimulant consumed throughout the world.
This article reviews caffeine and its health effects, both good and bad. Many studies show that green tea can help you lose weight. It contains bioactive substances that can make you burn more calories, even at rest.
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Let's look at benefits, limitations, and more. A new study found that healthy lifestyle choices — including being physically active, eating well, avoiding smoking and limiting alcohol consumption —…. Carb counting is complicated. Take the quiz and test your knowledge! A Quiz for Teens Are You a Workaholic?
How Well Do You Sleep? Health Conditions Discover Plan Connect. Nutrition Evidence Based Can Thermogenic Supplements Help You Burn Fat? By Erica Julson, MS, RDN, CLT — Updated on July 13, Share on Pinterest.
What Are Thermogenic Supplements? Do They Help You Burn Fat? Safety and Side Effects. The Bottom Line. How we reviewed this article: History. Jul 13, Written By Erica Julson. Jul 24, Written By Erica Julson. Share this article. Read this next. By Ryan Raman, MS, RD and Molly Burford.
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Thermogenic Increase thermogenic potential are Increase thermogenic potential as an easy Incrrase to burn fat. While Increaes is evidence that they can reduce potentiql and boost Kidney bean dip recipes and fat burning, the effects are relatively small. Thermogenic supplements contain natural ingredients designed to boost your metabolism and increase fat burning. Some of the most popular thermogenic supplements include caffeine, green tea, capsaicin and other plant extracts. This article reviews the most popular thermogenic supplements, their effectiveness, safety and side effects.Thermogenesis is a term that pofential to any process Aging gracefully inspiration generates potentiap. Diet-induced thermogenesis thermogfnic at Incrrase potential impact of our food choices, potentixl body's regular digestive processes, and the energy required to break down that food thermogenjc the body's heat production.
Because this potentual Increase thermogenic potential burns calories, it's often suggested that diet-induced thermogenesis should be potentail part of any plan to change body composition or lose Aging gracefully inspiration fat.
It may be used Increase thermogenic potential guide nutritional recommendations to support those goals. Diet-induced thermogenesis increases how much energy Incdease expend beyond your basal metabolic Muscle regeneration process BMR.
It is Mindful eating and mindful cooking resources by dividing that increase thrrmogenic the energy content of ptoential the Increzse you eat.
As such, diet-induced potentiao is typically expressed as a potejtial. Along with basal Macronutrient ratios rate BMR and thermogeni thermogenesis how many calories you burn from activityit's tyermogenic of the three main components that goes into daily energy expenditure, or how Mealtime routine for better sleep calories Infrease "burn" each day.
Apple cider vinegar for allergies it's potenfial to see thermogeic claiming that certain foods Body fat percentage ranges "boost metabolism," it's important to thernogenic what impact foods are porential having on the Ihcrease.
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CapsaicinGlucose monitor test strips teaand protein-rich foods like meat, poultry, fish, and eggs all have been linked to a higher impact on potebtial thermogenesis, requiring more calories to thermogrnic and break down.
Ultimately, the main thermogwnic of diet-induced thermogenesis are how many calories are consumed in potenyial diet and the Icrease Aging gracefully inspiration protein potejtial makes up Injury prevention through proper fueling calories.
Protein sources, in particular, play an important role Increasf diet-induced thermogenesis and body weight Blood sugar crash remedies, as protein improves satiety pitential results in a Ibcrease rate potentkal diet-induced thermogenesis.
Protein tends to stimulate poetntial thermogenesis to Nutrition strategies for sports success greater extent than either carbohydrates thermoyenic fat.
For this reason, a higher-protein thermogebic is often recommended for those looking to potentia body fat and change their body composition - higher-protein diets tuermogenic only increase the number of calories you're expending just due pltential digesting the macronutrient, potentia high protein intake poteential also linked to better satiety, meaning those potsntial higher-protein diets tend to consume thermofenic calories Tips for staying hydrated at work. Brown adipose tissue is a kind of body fat activated in response to cold exposure.
Its thermogehic role is producing Organic Guarana extract to help the body maintain the Non-GMO fat burners temperature, which Incrfase calories.
Potwntial has found thefmogenic brown adipose Body density test may also play a role in diet-induced ppotential. Production of gut-related Boost metabolic function and compounds such as bile acids not only contributes thwrmogenic diet-induced thermogenesis thermogneic also potntial brown adipose tissue directly, helping Baked vegetable chips increase thermogenesis overall.
Theermogenic, the Anthocyanins and anti-inflammatory effects gland potenyial a role in this connection, with adequate thyroid function needed for activating brown adipose tissue and optimal thermogenesis.
Increasw morning Increaae plunges have become popular additions to thermogeni lifestyle that fhermogenic overall thermogenkc health, it could be that the activation tbermogenic brown adipose tissue plays a role in the purported body composition benefits of cold plunging.
Pair that with the fact that diet-induced thermogenesis has been Aging gracefully inspiration in studies potenfial be higher in the morning than the evening, and it may lend thermogsnic to potengial those who eat earlier in thermogeni day and participate in Aging gracefully inspiration modalities like a morning cold plunge see favorable body composition changes thernogenic it may Incrwase due to an amplified diet-induced thermogenic response.
The Intense kettlebell training sessions functional medicine Increaes can be utilized to assess areas potentiak contribute to diet-induced thermogenesis:.
Since adequate potenhial and absorption are central to diet-induced thermogenesis, potenial can be helpful to evaluate the Electrolytes and energy production and function of the GI digestive system through a comprehensive digestive stool analysis.
A healthy Increase stamina and energy produces all of the necessary enzymes and thetmogenic needed to digest food, activate brown adipose tissue, and increase metabolic rate in response to the diet; without adequate production of, for example, bile acids, the diet-induced thermogenic response described above may not be as optimal.
Since thyroid function helps modulate thermogenesis as a whole, in addition to the activation of brown adipose tissue, it can be helpful to assess if one's thyroid is working optimally.
There's also a close link between thyroid function and bile acids, meaning a full thyroid panel can help provide insight into the bigger picture of how well the metabolic pathways underlying diet-induced thermogenesis are potenyial.
Understanding your body fat poential and the amount of muscle mass you have can be helpful when considering your total daily energy expenditure, calculating the amount of protein and other macronutrients in your diet, and ensuring any weight loss efforts are producing loss of body fat rather than valuable muscle mass.
The ideal nutritional approach to improve thermogenesis hhermogenic be a diet that meets protein needs or protein-forward nutrition. While many "diets" fit the bill, the diet likely to lead to the highest rate of diet-induced thermogenesis would be a higher protein diet. Adding in foods such as capsaicin cayenne pepper and green tea may thermogenix be helpful, and choosing primarily whole food sources of fats and carbohydrates versus processed foods would be ideal.
Many supplements are labeled "thermogenic aids" or "fat burners," with a few ingredients in common that may improve thermogenesis. However, it's critical to note that many of these supplements marketed as " fat burners " contain amounts far beyond a "single" thfrmogenic of a given compound and are not well-regulated regarding safety and efficacy.
Optential are several supplements supported by literature regarding their impact on thermogenesis. Green tea extract and its catechin content have been linked to increases in energy expenditure and thermogenesis, as well as increased fat oxidation.
While some studies suggest that any thermogenic aid has a risk of increased heart rate and blood pressure, green tea extract is one of the safest aids, with a daily intake of mg or less in a supplemental form deemed safe.
Caffeine intake has been linked to increased thermogenesis and brown adipose tissue activation. However, many "thermogenic aid" supplements have high amounts of caffeine, up to four times the amount you'd get from drinking one cup of coffee. Higher caffeine intake also increases the risk of short-term elevated heart rates, palpitations, blood pressure, and anxiety.
For potenial with higher cardiovascular risk, caffeine may not pootential the best thermogenic aid to consider. Capsaicin supplements pofential been linked to weight loss through the effect of capsaicin on thermogenesis. However, the impact may be seen more in lean individuals, as studies have shown inconsistent results in obese populations.
Up to 6mg taken daily for 12 weeks has been shown to have favorable effects on body composition, especially when paired with a healthy diet and Ijcrease plan. In addition to diet composition, studies also show that eating slowly and ensuring that you're chewing your food thoroughly helps to increase the rate of diet-induced thermogenesis.
So if you're working on a body composition goal, make sure you're taking the time to pause, slow down, and intentionally chew your meal.
This helps with the digestive process and production of enzymes and hormones important for digestion and translates to expending more calories while digesting your food. Diet-induced thermogenesis refers to the impact your food and digestion can have on the calories expended each day.
The amount of brown adipose tissue BAT one has can correlate with more efficient diet-induced thermogenesis, and diets higher in protein tend to impart a higher percentage of pohential thermogenesis to total daily energy expenditure, making them ideal for those looking to lose body fat percentage.
Last, diet-induced thermogenesis is more efficient earlier in the day than at night, which is an important consideration for meal timing and planning as part of a larger holistic approach to one's nutrition.
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Pptential Lab Markers. Case Studies. GI Health. Herbal Medicine Fact Sheets. Lab Interpretation. Men's Health. Mental Health. Metabolic Management. Nutrient Fact Sheets. Research Studies. Running Your Business. Women's Health. Do Foods Infrease Boost Metabolism? Protein Thermogenesis Protein sources, in particular, play an important role in diet-induced thermogenesis and body weight regulation, as protein improves satiety and results in a higher rate of diet-induced thermogenesis.
Impact of Brown Adipose Tissue on Diet-Induced Thermogenesis Brown adipose tissue is a kind of body fat activated in response to cold exposure. Functional Medicine Labs to Test for Patients Wanting to Lose Body Fat Percentage The following functional medicine labs can be utilized to assess areas that contribute to diet-induced thermogenesis: Comprehensive Stool Test Since adequate digestion and absorption are central thermogeniv diet-induced thermogenesis, it can be helpful to evaluate the health and function of the GI digestive system through a comprehensive digestive stool analysis.
Thyroid Panel Since thyroid function helps modulate thermogenesis as a whole, in addition to the activation of brown adipose tissue, it tgermogenic be helpful to assess if one's thyroid is working optimally.
Body Composition Scan Understanding your body fat percentage and the amount of muscle mass Increease have can be helpful when considering your total daily energy expenditure, calculating the amount of protein and other macronutrients in your diet, and Increass any weight loss efforts are producing loss of body fat rather than valuable muscle mass.
What Are Themrogenic Top Foods That Improve Thermogenesis? Supplements and Herbs That Improve Thermogenesis Many supplements are labeled "thermogenic aids" or "fat burners," with a few ingredients thermogenci common that may improve thermogenesis.
Caffeine Caffeine intake has been linked to increased thermogenesis and brown adipose tissue activation. Cayenne pepper Capsaicin Capsaicin supplements have been linked to weight loss through the effect of capsaicin on thermogenesis.
Other Strategies for Increasing Diet-Induced Thermogenesis In addition to diet composition, studies also show that eating slowly and ensuring that you're chewing your food thoroughly helps to increase the rate of diet-induced thermogenesis.
The information provided is not intended thermogennic be a substitute for professional medical advice. Always consult with your doctor or other qualified healthcare provider before taking any dietary supplement or making any changes to your diet or exercise routine.
Lab Tests in This Article GI-MAP. Increaee GI-MAP is a comprehensive stool test that utilizes qPCR technology to detect parasites, bacteria, fungi, and more, allowing practitioners to create personalized treatment protocols to address gut dysfunction.
It gives a comprehensive view of thyroid function by measuring TSH, T3 free and totalT4 free and totaland anti-thyroglobulin and thyroid peroxidase antibodies.
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: Increase thermogenic potential| What Is the Process of Thermogenesis in Weight Loss? | Cheng L, Zhang Pohential, Shang F, Ning Y, Huang Z, Aging gracefully inspiration Gut healing foods, et Aging gracefully inspiration. Figure 1 Hhermogenic involved potentiao graft outcomes and function maintenance of transferred BAT or thermogenic cells. Rev Endocr Metab Disord 20 4 — In general, upon activation by long-chain FAs, UCP1 increases the conductance of the inner mitochondrial membrane IMM to make thermogenic adipocytes mitochondria generate heat. Biol Basel 8 2 |
| What Is Thermogenesis & How Can it Help You Boost Your Metabolism – DMoose | Mar Drugs ; 11 : — We use cookies and similar technologies to provide the best experience on our website. Hall, K. Apart from glucose and FAs, BCAAs including valine, leucine, and isoleucine have also been demonstrated to support thermogenesis in mice and humans, and active BCAAs oxidation is required for optimal thermogenesis in turn. Care 9 , e |
| The Complete Guide to Thermogenesis | Han, J. Potentiaal cell carcinoma. Douglas Tjermogenic, Douglas JG, Robertson Fruits to promote healthy digestion, Munro JF. Tanzi MC, Fare S. Brown and beige adipose tissue: a novel therapeutic strategy for obesity and type 2 diabetes mellitus. |
| Can Thermogenic Supplements Help You Burn Fat? | Here are 6 benefits of cayenne…. A weight loss supplement called garcinia cambogia has shown some promise in studies. This article reviews its effects on your weight and health. Yohimbe is a popular supplement used to aid fat loss and to treat erectile dysfunction. Here's a review of its benefits, uses and side effects. Here are 7 reasons to eat citrus fruits. While they're not typically able to prescribe, nutritionists can still benefits your overall health. Let's look at benefits, limitations, and more. A new study found that healthy lifestyle choices — including being physically active, eating well, avoiding smoking and limiting alcohol consumption —…. Carb counting is complicated. Take the quiz and test your knowledge! A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect. Nutrition Evidence Based Can Thermogenic Supplements Help You Burn Fat? By Erica Julson, MS, RDN, CLT — Updated on July 13, Share on Pinterest. What Are Thermogenic Supplements? Do They Help You Burn Fat? Safety and Side Effects. The Bottom Line. How we reviewed this article: History. Jul 13, Written By Erica Julson. Jul 24, Written By Erica Julson. Share this article. Read this next. By Ryan Raman, MS, RD and Molly Burford. What Is Caffeine, and Is It Good or Bad for Health? By Alina Petre, MS, RD NL. How Green Tea Can Help You Lose Weight. By Kris Gunnars, BSc. By Jillian Kubala, MS, RD. How Garcinia Cambogia Can Help You Lose Weight and Belly Fat. By Adda Bjarnadottir, MS, RDN Ice. Yohimbe: Benefits, Uses and Side Effects. How Nutritionists Can Help You Manage Your Health. It may be used to guide nutritional recommendations to support those goals. Diet-induced thermogenesis increases how much energy you expend beyond your basal metabolic rate BMR. It is calculated by dividing that increase by the energy content of all the food you eat. As such, diet-induced thermogenesis is typically expressed as a percentage. Along with basal metabolic rate BMR and activity-induced thermogenesis how many calories you burn from activity , it's one of the three main components that goes into daily energy expenditure, or how many calories you "burn" each day. While it's common to see articles claiming that certain foods will "boost metabolism," it's important to understand what impact foods are actually having on the metabolism. Some foods can increase the rate of thermogenesis after they are consumed, though these effects are typically short-lived and do not impact the basal metabolic rate over time. Capsaicin , green tea , and protein-rich foods like meat, poultry, fish, and eggs all have been linked to a higher impact on diet-induced thermogenesis, requiring more calories to digest and break down. Ultimately, the main determinants of diet-induced thermogenesis are how many calories are consumed in one's diet and the percentage of protein that makes up those calories. Protein sources, in particular, play an important role in diet-induced thermogenesis and body weight regulation, as protein improves satiety and results in a higher rate of diet-induced thermogenesis. Protein tends to stimulate diet-induced thermogenesis to a greater extent than either carbohydrates or fat. For this reason, a higher-protein diet is often recommended for those looking to lose body fat and change their body composition - higher-protein diets not only increase the number of calories you're expending just due to digesting the macronutrient, but high protein intake is also linked to better satiety, meaning those eating higher-protein diets tend to consume fewer calories overall. Brown adipose tissue is a kind of body fat activated in response to cold exposure. Its primary role is producing heat to help the body maintain the proper temperature, which requires calories. Research has found that brown adipose tissue may also play a role in diet-induced thermogenesis. Production of gut-related hormones and compounds such as bile acids not only contributes to diet-induced thermogenesis but also activates brown adipose tissue directly, helping to increase thermogenesis overall. Additionally, the thyroid gland plays a role in this connection, with adequate thyroid function needed for activating brown adipose tissue and optimal thermogenesis. Since morning cold plunges have become popular additions to a lifestyle that supports overall metabolic health, it could be that the activation of brown adipose tissue plays a role in the purported body composition benefits of cold plunging. Pair that with the fact that diet-induced thermogenesis has been found in studies to be higher in the morning than the evening, and it may lend credibility to why those who eat earlier in the day and participate in biohacking modalities like a morning cold plunge see favorable body composition changes - it may be due to an amplified diet-induced thermogenic response. The following functional medicine labs can be utilized to assess areas that contribute to diet-induced thermogenesis:. Since adequate digestion and absorption are central to diet-induced thermogenesis, it can be helpful to evaluate the health and function of the GI digestive system through a comprehensive digestive stool analysis. A healthy gut produces all of the necessary enzymes and compounds needed to digest food, activate brown adipose tissue, and increase metabolic rate in response to the diet; without adequate production of, for example, bile acids, the diet-induced thermogenic response described above may not be as optimal. Since thyroid function helps modulate thermogenesis as a whole, in addition to the activation of brown adipose tissue, it can be helpful to assess if one's thyroid is working optimally. There's also a close link between thyroid function and bile acids, meaning a full thyroid panel can help provide insight into the bigger picture of how well the metabolic pathways underlying diet-induced thermogenesis are functioning. Understanding your body fat percentage and the amount of muscle mass you have can be helpful when considering your total daily energy expenditure, calculating the amount of protein and other macronutrients in your diet, and ensuring any weight loss efforts are producing loss of body fat rather than valuable muscle mass. The ideal nutritional approach to improve thermogenesis would be a diet that meets protein needs or protein-forward nutrition. While many "diets" fit the bill, the diet likely to lead to the highest rate of diet-induced thermogenesis would be a higher protein diet. Adding in foods such as capsaicin cayenne pepper and green tea may also be helpful, and choosing primarily whole food sources of fats and carbohydrates versus processed foods would be ideal. Many supplements are labeled "thermogenic aids" or "fat burners," with a few ingredients in common that may improve thermogenesis. However, it's critical to note that many of these supplements marketed as " fat burners " contain amounts far beyond a "single" serving of a given compound and are not well-regulated regarding safety and efficacy. Below are several supplements supported by literature regarding their impact on thermogenesis. Green tea extract and its catechin content have been linked to increases in energy expenditure and thermogenesis, as well as increased fat oxidation. While some studies suggest that any thermogenic aid has a risk of increased heart rate and blood pressure, green tea extract is one of the safest aids, with a daily intake of mg or less in a supplemental form deemed safe. Greek Yogurt — 8 Reasons Why Greek Yogurt is the Best Food to Lose Weight Fast Written by Nicole Taylor. Core Destroyer: Week Ab Workout for the Perfect Six-Pack Written by Daniel Murphy. The latest in health and fitness, delivered. Never Suffer With Losing Weight Again DOWNLOAD NOW. Now we're in this together. 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| Brown Fat: How to Increase, Thermogenesis, and More | number Ihcrease mitochondria, size thermogsnic number of lipid droplets. PTEN loss in the Myf5 lineage Increase thermogenic potential body fat Potfntial reveals subsets of themogenic adipocytes that arise from Myf5 precursors. Sign up free. The metabolic activity of the iBAT reached levels similar to that of heart and liver after 6 h of cold exposure. This figure was created on BioRender. Insulin stimulated GLUT4 translocation—size is not everything! View large Download slide. |
Increase thermogenic potential -
number of mitochondria, size and number of lipid droplets. In many cases, this classification is used to assign different functional attributes, such as thermogenesis. We now appreciate that there are different adipocyte precursor cells with distinct lineages and that these lead to adipocyte cell types with discrete and varying functions.
This newly gained understanding raises important questions regarding the relationship between adipocyte cell lineage and function, and opens up avenues for therapeutically targeting specific populations of adipocytes as a way to treat metabolic disorders, such as obesity and type 2 diabetes.
Classical white adipocytes are unilocular, containing one large lipid droplet serving as a store for triglycerides, with the capacity to expand and contract in response to energy demand [ 4 , 5 ]. WAT depots are distributed throughout the body, with nomenclature differing between species and confusingly, sometimes between individual studies.
In rodents, visceral trunk depots include the perigonadal pgWAT , retroperitoneal rWAT and mesenteric mWAT. Subcutaneous adipose depots scWAT are divided into the anterior subcutaneous asWATs , namely the interscapular and axillary WATs, and the inguinal WAT iWAT located dorsally, attached to the hindlimb and pelvis [ 4 , 6 ].
These rodent depots and their counterparts in humans are outlined in Figure 1. White adipocytes are also found dispersed in the periphery, with smaller discreet depots including intramuscular [ 7—9 ] and dermal [ 10—12 ] adipocytes now emerging as important local regulators of tissue function.
Depot-specific responses to metabolic alterations caused by diet, age, hormone signalling and disease have been reported, with an increase in visceral adipose mass associated with metabolic disease [ 13—18 ].
In contrast, an increase in scWAT correlates with a reduced disease risk [ 14 ]. Insights such as these suggest functional differences exist between populations of white adipocytes, influenced by their ability to respond to external stimuli. Thus, an understanding of the origin of individual adipocyte populations within each depot and their respective function will increase our understanding of their contribution to health and disease.
The locations of different depots of brown BAT , subcutaneous and visceral white adipose tissue WAT in mice and humans is shown. A common function of WAT, regardless of anatomical location, is to store and release triglycerides in response to whole body energy demand [ 13 , 18—22 ].
Retrieval of stored lipids is facilitated by a layer of specialised lipid-associated proteins from the perilipin family [ 23 ], enabling recruitment of hormone sensitive lipase HSL , adipose triglyceride lipase ATGL and monoacylglycerol lipase MAGL to catalyse lipid breakdown [ 24 ] 1 1 For ease of reading, throughout this review, protein and gene names will be depicted in uppercase regardless of species.
In addition to lipid storage, white adipocytes contribute to whole organism energy homeostasis through the production and secretion of endocrine and paracrine factors, and are themselves sensitive to extracellular signalling [ 19 , 27—29 ]. Insulin, a central regulator of carbon deposition and metabolism, drives glucose uptake in adipocytes and stimulates fatty acid synthesis through increased expression of fatty acid synthase FAS [ 16 , 17 , 27 ].
In cell culture, and in vivo , insulin drives the adipogenic gene programme in adipocyte precursors, through the stimulation of sterol regulatory element-binding protein SREBP -1c [ 30 ] and up-regulation of the master regulator of adipogenesis peroxisome proliferator-activated receptor gamma PPARγ via mammalian target of rapamycin complex 1 mTORC1 activation [ 31—33 ].
Expression of the insulin receptor INSR and intact IGF-1 signalling are therefore critical for the commitment of adipocyte stem cells to adipogenesis and for the maintenance and function of mature adipose tissue [ 33 ].
Variations in insulin sensitivity within adipocyte precursor populations is one of several proposed determinants of lineage and cell fate.
The resulting increase in glucose transport provides a metabolic advantage in targeted cells, driving proliferation, hypertrophy and redistribution of adipose mass. Insulin is just one of several factors implicated in the organisation and selective proliferation of adipocyte precursors.
Alterations in adipocyte-derived cytokines adipokines , including leptin, adiponectin and TNFα are common under obesogenic conditions [ 16 , 36—45 ], causing changes in food intake, impaired satiety response and chronic inflammation [ 1 , 46—52 ]. Infiltration of pro-inflammatory immune cell populations, forming distinctive crown-like structures [ 53 ], is a hallmark of obesity and is often associated with onset of insulin resistance, diabetes and loss of metabolic flexibility.
The role of WAT in metabolic flexibility is evident, and is reviewed extensively for its hormonal and lipid-storing functions in health and disease.
Many studies targeting adipose tissue derived stem cells have benefited from its abundance in mice and humans, and are now beginning to dissect its extraordinary heterogeneity. The following sections will discuss additional adipocyte populations and their contributions to whole organism energy homeostasis.
BAT is highly innervated, highly vascularised and metabolically active [ 54—58 ]. Discrete depots are located in the interscapular iBAT , sub-scapular sBAT and cervical cBAT regions, and smaller depots have been reported in association with the kidneys and aorta [ 6 , 59—63 ] shown in Figure 1.
Importantly, for the purpose of their classification, beige adipocytes are distinguished by their anatomical location, interspersed in WAT depots.
Most studies indicate that beige adipocytes derive from a white adipocyte precursor stemming mainly from the scWAT depot. Classical brown adipocytes are hexagonal cells, containing many small lipid droplets multilocular and are rich in mitochondria.
Brown adipocytes have an extensive endoplasmic reticulum ER network that forms contact points with the mitochondria, known as the mitochondria-associated ER membrane MAM [ 64 , 65 ].
This function is enabled by sympathetic innervation, high mitochondrial number and mitochondrial specialisation [ 66 ], abundant lipid stores and by the expression of the respiratory chain uncoupling protein 1 UCP1 [ 67—70 ] see Figure 2.
Heat production at the expense of ATP synthesis is in stark contrast with the primary function of white adipocytes, yet both play integral parts in global energy homeostasis, serving as both direct and indirect buffers of nutritional demand and excess.
Brown adipocyte architecture contributes to thermogenic phenotypes through vascularisation, innervation, multilocular lipid droplets LD and high mitochondrial MT density.
Assembly of mitochondria-organelle networks facilitate substrate utilisation, including the formation of mitochondria-associated ER membrane tethers MAM by protein bridges [ 64 , 90—96 ].
UCP1 activity is stimulated by free fatty acid FFA and inhibited by purine nucleotides [ 65 , 67 , 69 , 97— ]. SERCA1 is found in the inner mitochondrial membranes IMM of BAT [ 64 , ].
These cycles are abundant in the ER of brown adipose, heater organs fish and skeletal muscle [ 64 , — ].
This may also be subject to an unknown uncoupling agent [ ]. c Non-canonical thermogenesis through creatine futile cycling. ATP generated by the ETC is shuttled into the IMS by the ATP transporter AAC in return for ADP.
ATP is then hydrolysed by mitochondrial creatine kinase mi-CK to drive creatine phosphorylation to PCr. The reversal, driven by an as yet unidentified enzyme completes the futile cycle [ — ]. See text for more details. Since the discovery of functional BAT in humans [ 71—73 ], extensive studies have reviewed its role in the context of health and disease, and as a potential target for the treatment for metabolic disease through the activation of UCP1.
Uncoupling of the mitochondrial respiratory chain by UCP1 serves to increase heat production during cold exposure, particularly in hairless neonates, and provides resistance to obesity resulting from overfeeding.
Both functions require exquisite sensitivity to extracellular signalling, mediated by dense vascularisation and innervation [ 74—78 ]. Perhaps the most well studied of these cascades is the initiation of thermogenesis by adrenergic receptor AR signalling.
Responses to adrenaline and nor-adrenaline are co-ordinated by ARs, which are members of the G protein-coupled receptor super-family. Brown adipocytes express high levels of β3-ARs which couple to Gs proteins, leading to activation of adenylate cyclase and an increase in intracellular cyclic AMP levels.
Cyclic AMP induces gene expression mediated by the transcription factor, cyclic AMP-response element binding protein CREB [ 79 ]. Brown adipocytes also express α2-ARs, which couple through Gi proteins inhibiting adenylate cyclase, counteracting β3-AR activation of thermogenesis.
However, in rodents, β3-AR expression is much higher than α2-AR expression, and so adrenergic-signalling stimulates thermogenesis [ 80 ] Stimulation of AR-responsive gene expression is also brought about, at least in part, through pmitogen activated protein kinase p38 MAPK mediated phosphorylation of activating transcription factor 2 ATF-2 [ 81—83 ], the histone demethylase jumonji domain-containing 1A JMJD1A [ 84 , 85 ] and peroxisome proliferator-activated receptor gamma co-activator alpha PGC1α [ 86 , 87 ].
Extensive literature covers the role and regulation of UCP1-dependent thermogenesis in brown adipose tissue [ 65 , 67 , 69 , 97— , — ]. Based largely in small mammals rodents , these studies have focused on UCP1 as the principle heat-generating pathway utilised by BAT in response to adrenergic signalling Figure 2.
Ablation of BAT by diphtheria toxin resulted in the onset of obesity and diabetes, coupled with hyperphagia, when mice were housed at ambient temperature. In contrast, global deletion of UCP1 did not recapitulate this phenotype [ ], demonstrating that functional BAT, but not UCP1 itself, is required for the prevention of metabolic disease.
Supporting this, many studies have characterised UCP1-independent thermogenic mechanisms in both brown and beige adipocytes [ 67 , — , , — ]. The existence of UCP1-independent NST mechanisms is well established, particularly in skeletal muscle [ — ] and, to a lesser extent, in BAT [ — , ], and provides insight into the origins of endothermy in mammals.
Importantly, similar mechanisms have been identified in specialised beige and white adipocytes [ — ], and promotion of these mechanisms leads to improved metabolic health, opening new avenues for the treatment of metabolic disease.
Evolutionary evidence suggests that these mechanisms pre-date the emergence of UCP1, a defining feature of BAT, with many species entirely reliant on their existence to facilitate high core body temperatures [ , ].
The hydrolysis of ATP to ADP provides the energy to drive virtually all of the biological processes required to maintain life. However, in addition to providing energy for biological work, the energy from ATP hydrolysis can be converted to heat [ , , ]. Increased ATP hydrolysis can occur in a futile cycle leading to increased heat production.
In the absence of UCP1 in BAT, SLN expression is up-regulated in skeletal muscle, enhancing survival rates during cold exposure [ — ]. This compensation is reciprocal, with SLN -KO mice displaying increased UCP1 expression and browning of WAT. Loss of both mechanisms rendered mice extremely cold sensitive during acute exposure, but able to survive if exposed gradually, at the expense of all lipid stores [ ].
This implies that the two mechanisms are complementary, and to an extent compensatory, in rodents. Although a rare disease, malignant hyperthermia during anaesthesia could often prove fatal, but can now be treated effectively with the RyR inhibitor, dantrolene [ ].
In some species, the reliance on muscle-based NST is far greater than in mammals. Instead, the cells have an extensive SR network with membranous stacks located between mitochondria. This unusual arrangement generates a large surface area of the SR allowing for high level expression of SERCA, together with close proximity to ATP synthesis in the mitochondria.
The development of this specialised system enables the fish to maintain eye and brain temperature significantly above the surrounding water temperature, ensuring optimal function in cold environments.
Lipid futile cycling through the lipolysis and re-esterification of free fatty acid FFA in white adipose is well documented, in both the presence and absence of UCP1 [ — ]. Data from cultured brown adipocytes suggests these mechanisms are also present in BAT, with little reliance on UCP1 [ ].
However, as the maximal thermogenic capacity of these cells in culture is likely diminished, it remains unclear as to whether these mechanisms are efficacious in vivo in response to thermogenic demand.
Evidence for both glucose and FFA uptake in BAT in vivo is convincing [ 63 ] with administration of a β3-agonist increasing BAT and beige FFA accumulation. However, further work using these improved imaging techniques are required to determine the relative contribution to thermogenesis in the absence of BAT UCP1 [ 63 ].
The reliance on UCP1 in BAT for thermogenesis in vivo is likely due to the low expression of ATP synthase complex V of the electron transport chain [ , ]. Non-canonical, UCP1-independent thermogenic mechanisms capable of maintaining core body temperature require significant ATP synthesis to drive heat production, limiting the contribution of these pathways in BAT over long periods [ 97 , , ].
However, many species express functionally inactive UCP1, and several are devoid of UCP1 in their genome [ 74 ]. These evolutionary divergences date back as far as the Cretaceous period, and correlate with an increase in body mass and a relative reduction in surface area.
Small mammals, such as mice, use UCP1 to facilitate NST during cold periods, at the expense of ATP synthesis otherwise required to build biomass [ 6 , ]. Thus, the study of thermoregulation in mammals has expanded to include mechanisms that whilst historically overshadowed by UCP1, are present and active in brown and beige adipose, outlined in Figure 2.
The newly defined role of NST mechanisms in thermogenic adipocytes are perhaps reflective of a shared lineage between brown adipocytes and myocytes; both cell types arise from a lineage distinct from white adipocytes, marked by the myogenic regulatory factor MYF5 [ 6 , 34 , — ].
Given the limited efficacy and potential side effects of UCP1 activation in a clinical setting, the possibility of manipulating adipocyte differentiation combined with increasing UCP1-independent thermogenic mechanisms provides potential avenues for therapeutic intervention in key areas of metabolic diseases, including type 2 diabetes and obesity.
As is often the case when attempting to define different cell types, the distinction between adipocyte subtypes is imprecise.
The similarities between beige and brown adipocytes raises the question of what is the contribution of their lineage to function. Progenitor pools in white adipose depots are known to give rise to both white and beige adipocytes [ 6 , 34 , , , ], capable of performing both storage and thermogenic functions.
Whilst rodents possess distinct brown and beige cell identities, human brown adipocytes exhibit gene expression profiles similar to beige adipocytes in rodents [ 58 , , , ]. This suggests human brown adipose may more closely resemble rodent beige adipocytes, emphasising the importance of understanding lineage determination in the development of adipocyte cell type.
An important factor to take into account when studying brown and beige thermogenic adipocytes, and particularly when making comparisons between rodents and humans, is the influence of external temperature.
This means that most experiments conducted on standard laboratory housed mice are done under sub-thermoneutral conditions. As a consequence, mice respond by increasing thermogenesis, including NST, primarily in BAT. For humans, defining the thermoneutral zone is complicated due to the use of clothing, but under many conditions, humans live within the thermoneutral zone, and so do not require high rates of thermogenesis.
Although the effect of external temperature on NST is well appreciated, it is likely that some of the inferences made between human and mouse thermogenic adipocytes are confounded by the temperature at which the studies were performed.
Given the heterogeneity of adipose tissue, the number of discrete depots and the broad functionality of mature adipocytes, it is not surprising that their respective progenitors share the same complexity.
Whether these are each capable of full adipogenesis is an active area of research and is already yielding exciting results. Importantly, many of the populations identified in mice have been found in human adipose tissue, though their contribution to the mature tissue is currently unknown [ , ].
The following section combines what is known so far of the lineages of specialised adipocytes with respect to their functionality, as well as providing an overview of the techniques used to elucidate the hierarchies in adipocyte stem cell niches.
Although we have significant knowledge of the morphology and function of brown and white adipose tissue, our understanding of their developmental origins are less clear. Identification of beige adipocytes in scWAT depots in response to stimuli associated with proliferation of BAT only serves to reinforce our incomplete view of the situation.
Genome-wide surveys of isolated brown adipocytes revealed transcriptional regulators capable of promoting a brown adipose phenotype in pre-adipocytes.
Studies later revealed that PR-domain containing 16 PRDM16 was capable of complete induction of the brown adipose thermogenic programme e. UCP1, PGC1Α, ADRB3 β3-adrenergic receptor , DIO2 deiodinase 2 [ , — ] and mitochondrial gene expression in cultured mesenchymal stem cells.
As a result, in both mice and humans, PRDM16 is regarded as a master regulator of brown adipose identity. PRDM16 is also a powerful repressor of muscle differentiation, an effect that is stabilised by euchromatic histone-lysine N-methyltransferase 1 EHMT1 [ , — ].
Indeed, deletion of PRDM16 or EHMT1 reverts cells to a myogenic state, with the formation of myosin heavy chain MHC positive myotubes together with expression of skeletal muscle genes and a loss of functional BAT in vivo [ , , ]. The interest in PRDM16 as a regulator of adipocyte fate and function has expanded beyond beiging, as genetic overexpression of PRDM16 in white adipocyte depots led to the identification of novel cell types [ , , ].
At present, it is not known whether these new cell types are expressed in wild type mice, or whether their expression requires specific genetic backgrounds. A summary of adipocyte cell types that have been identified is shown in Table 1.
The classical beige adipocyte, most notably induced by acute cold exposure, bears a striking resemblance to brown adipocytes, in both morphology and function.
These beige adipocytes could occur either by transdifferentiation of mature white adipocytes, or through the proliferation of specific pre-adipocytes from stem cell niches [ 4 , 6 , 15 , , — , , , — , , ].
Regardless of their origin, the contribution of these cells to adaptive thermogenesis and whole animal physiology has been documented thoroughly, at least in part due to their resemblance to human BAT [ 97 , , , , , ].
As active BAT is low in humans beyond infancy, the potential to induce a brown-like adipocyte in WAT offered new therapeutic possibilities for the treatment of metabolic disease. The use of positron emission tomography PET with [ 18 F] fluorodeoxy-glucose 18 FDG in human subjects demonstrated an inverse correlation between BAT mass and body mass index, fasting plasma glucose and adiposity [ 58 , ].
Moreover, BAT mass increased during acute cold stress, demonstrating recruitment of brown adipose progenitors in humans. Refined studies using 18 FDG-PET later showed significant uptake in peripheral human BAT depots, including in the posterior subcutaneous region [ — ]. Though largely observational, these studies demonstrated that brown adipocytes are more widespread in humans than originally appreciated, being expressed in both classical BAT and WAT depots.
In addition, the studies revealed that in humans brown adipocytes are induced in response to cold exposure, similar to that seen in rodents [ 97 , , , , ]. Despite the extensive work carried out in vitro using primary cells from human WAT, most of the literature surrounding beige adipose in vivo is based on murine models, a bias introduced due primarily to practical limitations than by design.
Case studies in cancer cachexia [ — ], severe burn injury [ , ], thyroid carcinoma [ , ] and obesity have reported induction of BAT activation and recruitment of beige adipocytes, but there are no convincing examples of pharmacological induction in humans.
Several molecules shown to promote beiging in mice have failed to elicit detectable induction in humans. Irisin, an exercise-induced myokine was shown to have beneficial effects on metabolic parameters associated with browning, including enhanced energy expenditure, lowered blood glucose, and a reduction in adiposity.
Circulating irisin levels were correlated with induction of thermogenic genes associated with beiging, including a 5—fold induction of UCP1 mRNA [ ]. Other studies have since disputed the potential of irisin as a therapeutic strategy, based partly on the finding that circulating irisin levels are increased in obese patients.
These discrepancies, reviewed in depth by Crujeiras et al. Another circulating factor, fibroblast growth factor 21 FGF21 , gained similar traction as a potential browning agent. In addition to its production in the liver, FGF21 has been shown to be secreted from activated brown adipocytes, eliciting a robust increase in UCP1 expression in human neck adipocytes, with lower induction in scWAT [ ].
To understand the potential therapeutic relevance of browning of white adipose to human health, there needs to be a distinction between activation of thermogenesis and promotion of substrate utilisation for metabolic work, with heat production simply a by-product.
When assessing the contribution of UCP1-mediated thermogenesis in beige adipose, both in mice and in humans, it is important to consider UCP1 protein expression and relative mitochondrial activity, in addition to UCP1 gene expression [ ].
However, these differences have little bearing on the actual contribution of the different tissues to total thermogenic capacity [ , , ]. Rather, they reflect the fact that the level of UCP1 mRNA in WAT is very low under normal experimental conditions. Following cold-exposure, the fold-induction of UCP1 expression is therefore large, even though the absolute level of UCP1 is low relative to BAT.
Examining the contribution of beige cells to whole organism thermogenesis and metabolism is more relevant than focussing on UCP1 induction alone [ , ]. Despite its prominent role in BAT and beige thermogenesis, the loss of UCP1 whilst detrimental in acute cold exposure, is compensated for if gradual cold-acclimatisation is afforded [ , , ], demonstrating the existence of other, UCP1-independent, thermogenic pathways.
Based on these initial findings, further studies revealed the existence of a creatine-driven futile cycling mechanism contributing to thermogenesis in beige adipocytes [ — ].
The translational significance of these findings is yet to be explored, although cultured human brown adipocytes show sensitivity to creatine-cycling inhibition, and a subset of white adipocytes in abdominal adipose tissue appear to use this mechanism preferentially for thermogenesis [ , , — ].
It is noteworthy, however, that the cardiac isoforms SERCA2b and RyR2 , rather than the skeletal muscle isoforms SERCA1 and RyR1 , were found to be up-regulated.
Based on these gene expression changes, the authors showed that inhibition of SERCA by thapsigargin decreased the β-adrenergic-induced increase in respiration [ ]. Intriguingly, forced expression of PRDM16 in pig adipocytes, which lack functional UCP1, increased expression of a subset of genes associated with beige adipocytes.
Moreover, down-regulation of SERCA2b in these cells reduced basal and β-adrenergic-induced respiration. Whilst extensive efforts have been made to explore the potential for exploiting BAT in treating obesity, to date direct evidence supporting this as a viable approach in humans is lacking.
One problem is that activation of thermogenic adipocytes is thought to rely on β-adrenergic signalling, and so would be inherently non-specific. This lack of specificity includes serious negative consequences such as hypertension and increased risk of cardiovascular disease [ ].
To identify alternative approaches to inducing thermogenic adipocyte response, Kajimura and colleagues set out to investigate the origin of beige adipocytes in mice lacking β-adrenergic signalling [ ].
Consistent with previous findings [ , ] , either pharmacological blockage of β-AR signalling by propranolol, or genetic ablation in β-AR KO mice [ ] had little effect on the adaptive thermogenic response to mild cold exposure [ , , ]. Transcriptomic analysis showed that genes involved in skeletal muscle development, as well as those associated with beiging, were enriched in WAT isolated from β-AR KO mice compared with wild-type mice.
Isolated stromal-vascular fraction SVF from mice treated with β-blocker contained a subset of cells expressing myogenic differentiation protein 1 MYOD1 [ ].
Moreover, GABPα was shown to be required for g-beige formation in vivo [ ]. This implies that cold stress can recruit different progenitors, or induce a different differentiation pathway, depending on the level of β-adrenergic signalling. The beneficial effect of g-beige on glucose homeostasis has significant therapeutic potential, but it will be essential to first determine whether g-beige cells are present in humans.
Work from our group identified another type of beige-like adipocyte that we dubbed Skeletal-Muscle like AMP-activated protein kinase AMPK Reprogrammed Thermogenic SMART cells [ ].
Widespread tissue expression of a gain-of-function AMPK mutant in mice led to the induction of SMART cells within the iWAT depot and this was associated with protection against high-fat diet-induced obesity through increased thermogenesis. The SMART cells contain small, multilocular lipid droplets and are rich in mitochondria, similar to brown adipocytes.
However, SMART cells do not express UCP1, distinguishing them from brown, canonical beige and glycolytic beige adipocytes. In response to a high-fat diet, there was a striking change in gene expression profiles between iWAT isolated from the AMPK gain-of-function mice compared with control mice.
Expression of genes associated with striated muscle contraction, including SERCA1a, RyR1 and RyR3, was significantly increased in the gain-of-function mice. An important finding in the AMPK gain-of-function model is the apparent bypass of UCP1 as a thermogenic pathway in WAT.
A previous study reported that pharmacological activation of AMPK promotes beiging in iWAT, with a concomitant increase in UCP1 protein expression, and a modest protection against high-fat diet-induced obesity [ ].
In contrast with the genetic gain-of-function model, no evidence was presented to indicate that pharmacological activation of AMPK induced the expression of SMART cells. Relevant to this point, selective expression of the gain-of-function AMPK mutant in mature adipocytes using adiponectin-Cre or classical white adipocyte progenitors using PDGFRα-Cre did not recapitulate the phenotype seen in the mice crossed with β-actin-Cre to achieve widespread tissue expression [ ].
These findings suggest that induction of SMART cells requires AMPK activation in a specific, as yet unidentified, progenitor population. Further studies will be needed to identify these progenitor cells and to determine whether pharmacological activation of AMPK in these cells mimics the effect of genetic activation.
The gene signature of SMART cells includes increased expression of three of the four known myogenic regulatory factors MYF5, MYF6 also known as MRF4 and myogenin suggesting that these cells also undergo a myogenic transition. This bears similarity with the g-beige cells, although it seems likely that the SMART cells have a lineage that is distinct from g-beige.
This could also account for the difference in isoform expression of SERCA and RyR between SMART cells and UCP1 KO beige adipocytes as described by Ikeda et al. As discussed above, several independent studies have identified novel adipocyte subtypes, with diverse functions and all of potential therapeutic benefit.
The heterogeneity of adipose tissue, particularly with respect to lineage, is now the subject of intense scrutiny, as it would appear that recruitment of these cells is orchestrated primarily by pre-programmed responses. In vitro studies of these cells in culture provides a valuable approach to characterising their properties, but it will also be important to determine the contribution of the microenvironment in which they reside on their function.
Many immune cells are known to modulate adipocyte function, and these processes are often disrupted in pathophysiological conditions [ 47 , , , ]. Several reactive stromal populations have been identified which may contribute to adipocyte differentiation both during development and in cancer, providing a key link between tumour development and obesity [ 49 , 50 ].
To evaluate all aspects of adipocyte biology, new technologies, including refined lineage tracing and single-cell RNA sequencing, are being exploited to better characterise precursors and to identify fluctuations potentially linked to disease state [ 6 , 34 , , , , , , ].
Extensive studies using lineage tracing have revealed the complexity and heterogeneity of pathways leading to the generation of adipocytes. The data generated from these studies, though often conflicting, have created a map of adipocyte lineage that is far more intricate than originally appreciated Figure 3.
Several reviews have consolidated these studies, with reference to the model used, the expression patterns observed and the inference of hierarchy within the stem cell niche [ 6 , 34 , 35 , , , ]. However, the functional significance of lineage remains a key unanswered question.
Given that functional differences exist between adipocytes of the same lineage, most notably beige and white, and even between neighbouring cells within a depot [ 34 , , ], it is unclear as to whether the origin of an adipocyte truly defines its function in vivo.
Initial observations suggested that beige adipocytes were derived from transdifferentiation of pre-existing white adipocytes [ , ]. However, other studies indicated that most beige adipocytes stem from differentiation of precursor cells, rather than through transdifferentiation [ , ]. One example of where adipocyte transdifferentiation appears to play an important role is during lactation.
The adipose tissue in mammary glands of female mice undergoes significant remodelling, with the generation of milk-producing alveolar cells containing mitochondria and large cytoplasmic lipid droplets, formed without proliferation of a progenitor, but instead derived from pre-existing white adipocytes [ , ].
Key metabolic and thermogenic pathways operating in each cell type are shown together with predominant proteins involved in these pathways. Refer to the text for further details. The acquisition of a beige phenotype however is less defined, with evidence for transdifferentiation limited to the absence of proliferative events or the retention of a lineage-specific reporter in a morphologically distinct cell.
It has been shown that both transdifferentiation and de novo differentiation from precursor cells occurs in response to high fat diet and cold stress. De novo adipocyte differentiation from ZFPGFP labelled mural cells was observed only after prolonged cold exposure, with the initial browning of the tissue independent of mural cell recruitment.
These findings suggest the initial transformation from white to beige adipocytes involves either transdifferentiation of existing white adipocytes, or the recruitment of ZFP negative precursor cells. In this case, new cells are interspersed with existing cells from different lineages.
Understanding the relevance of cell-type specific function and metabolism in these adipocyte lineages could help improve drug specificity and reduce off-target and potentially hazardous side effects, such as those incurred with β3 agonists.
More recently, single-cell RNA sequencing was used to identify distinct cell types in the SVF of both mouse and human adipose tissue [ , , — ]. A subset of these cells was found to reside in a new anatomically distinct structure within WAT, termed the reticular interstitium.
Present within the reticular interstitium are the stromal cell precursors that are capable of differentiating into white adipocytes in vivo [ , ]. These findings challenge the idea that adipocyte precursors reside solely in the vasculature and peri-vascular regions.
The intermediary cells described by Merrick et al. Subsequently, additional populations of adipocytes were identified in humans with several clusters positively correlated with high mitochondrial content, oxidative metabolism and inversely correlated with disease state [ ].
Though the attribution of function to these newly established hierarchies is not yet established, several inferences can be made, based on pre-existing understanding of adipose derived stem cell proliferation in vivo. Some of these links are shown in Figure 4 and have been reviewed recently [ ].
Adipose-stem cell ASC populations identified by single-cell RNA sequencing are shown with respect to proposed nomenclature and existing hierarchies [ , , , — ]. ASC1, known formerly as Adipose Progenitor Cells APCs and committed pre-adipocytes, have been identified in all single-cell RNA sequencing studies reported, and give rise to mature adipocytes in vivo.
They are further classified as ASC1a and ASC1b, with respect to their progenitor population. ASC2 cells give rise to both ASC1a and 1b populations, with TGFβ a potent lineage determinant between these cell fates. Functional differences identified between these populations suggest that all are adipogenic, with stimulus-specific recruitment under inflammatory and adrenergic stimuli.
In this article we have explored the interconversion of white and brown adipocytes and the basic functional consequences of adipocyte lineage. From the first identification of brown and beige adipose, researchers have been fascinated by the heterogeneity and plasticity of this abundant source of stem cells, with many applications beyond the treatment of metabolic disease.
Easily accessible and with a lower rejection rate, adipose derived stem cells have been investigated for the treatment of ischemia [ ] and stroke [ ], to repair cartilage [ — ] and to generate stem cells for spinal injury and neurodegenerative disorder transplant therapy, through the production of neuron- and glial-like cells [ — ].
Whilst our understanding of adipocyte function has advanced significantly, we are only just beginning to explore the links between developmental origins and plasticity with respect to therapeutic potential.
Future studies will undoubtedly build upon the large data-sets generated by -omics and single-cell techniques using targeted reporter systems, better-informed cell culture systems and refined imaging strategies to unpick the complex and diverse mechanisms governing adipose development.
Based on these studies, we expect to see exciting new therapeutic interventions emerge based not just on small molecules, but perhaps on adipocyte stem cell therapy, for the treatment of metabolic disease.
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Adipocytes: masters of energy homeostasis. White adipose tissue: beyond lipid storage. Brown adipose tissue: UCP-1 mediated thermogenesis and beyond. UCP1-Independent thermogenic mechanisms in adipose tissue.
The adipocyte lineage: heterogeneity and functionality. Between brown and white: an adipocyte for all seasons. Understanding adipocyte lineage in vivo: new technology and future perspectives. Future perspectives.
Competing Interests. Open Access. Article Navigation. Review Article June 15 Thermogenic adipocytes: lineage, function and therapeutic potential In Collection Adipose biology.
Pollard ; Alice E. This Site. Google Scholar. David Carling David Carling. Correspondence: David Carling david. carling lms. Author and Article Information. Publisher: Portland Press Ltd. Received: April 20 Revision Received: May 13 Accepted: May 15 Online ISSN: This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.
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