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As a dynamic endocrine organ, white adipose tissue (WAT) stores lipids and plays a critical role in maintaining whole-body energy homeostasis and insulin sensitivity. A large group of the population over 65 years old suffer from increased WAT mass, especially in the visceral location. Visceral adiposity accelerates aging through promoting age-associated chronic conditions, significantly shortening life expectancy. Unlike WAT, brown adipose tissue (BAT) functions as an effective energy sink that burns and disposes of excess lipids and glucose upon activation of thermogenesis. Unfortunately, the thermogenic activity of BAT declines during aging. New appreciation of cellular and functional remodeling of WAT and BAT during aging has emerged in recent years. Efforts are underway to explore the potential underlying mechanisms behind these age-associated alterations in WAT and BAT and the impact of these alterations on whole-body metabolism. Lastly, it is intriguing to translate our knowledge obtained from animal models to the clinic to prevent and treat age-associated metabolic disorders. © 2022 American Physiological Society. Compr Physiol 12: 4119-4132, 2022., (Copyright © 2022 American Physiological Society. All rights reserved.)

Brown adipose tissue (BAT) is well known to burn calories through uncoupled respiration, producing heat to maintain body temperature. This 'calorie wasting' feature makes BAT a special tissue, which can function as an 'energy sink' in mammals. While a combination of high energy intake and low energy expenditure is the leading cause of overweight and obesity in modern society, activating a safe 'energy sink' has been proposed as a promising obesity treatment strategy. Metabolically, lipids and glucose have been viewed as the major energy substrates in BAT, while succinate, lactate, branched-chain amino acids, and other metabolites can also serve as energy substrates for thermogenesis. Since the cataplerotic and anaplerotic reactions of these metabolites interconnect with each other, BAT relies on its dynamic, flexible, and complex metabolism to support its special function. In this review, we summarize how BAT orchestrates the metabolic utilization of various nutrients to support thermogenesis and contributes to whole-body metabolic homeostasis., (© 2021 Federation of European Biochemical Societies.)

Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high-fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes.

The transcriptional regulators Ebf2 and Prdm16 establish and maintain the brown and/or beige fat cell identity. However, the mechanisms operating in white adipocytes to suppress the thermogenic gene program and maintain an energy-storing phenotype are less understood. Here, we report that the transcriptional regulator Zfp423 is critical for maintaining white adipocyte identity through suppression of the thermogenic gene program. Zfp423 expression is enriched in white versus brown adipocytes and suppressed upon cold exposure. Doxycycline-inducible inactivation of Zfp423 in mature adipocytes, combined with β-adrenergic stimulation, triggers a conversion of differentiated adiponectin-expressing inguinal and gonadal adipocytes into beige-like adipocytes; this reprogramming event is sufficient to prevent and reverse diet-induced obesity and insulin resistance. Mechanistically, Zfp423 acts in adipocytes to inhibit the activity of Ebf2 and suppress Prdm16 activation. These data identify Zfp423 as a molecular brake on adipocyte thermogenesis and suggest a therapeutic strategy to unlock the thermogenic potential of white adipocytes in obesity., Competing Interests: Conflicting interests statement. The authors declare that they have no competing financial interests., (Copyright © 2016 Elsevier Inc. All rights reserved.)