Contribution of adipogenesis to healthy adipose tissue expansion in obesity Lavanya Vishvanath, Rana K. Gupta J Clin Invest. 2019;129(10):4022-4031. https://doi.org/10.1172/JCI129191. Review Series The manner in which white adipose tissue (WAT) expands and remodels directly impacts the risk of developing metabolic syndrome in obesity. Preferential accumulation of visceral WAT is associated with increased risk for insulin resistance, whereas subcutaneous WAT expansion is protective. Moreover, pathologic WAT remodeling, typically characterized by adipocyte hypertrophy, chronic inflammation, and fibrosis, is associated with insulin resistance. Healthy WAT expansion, observed in the “metabolically healthy” obese, is generally associated with the presence of smaller and more numerous adipocytes, along with lower degrees of inflammation and fibrosis. Here, we highlight recent human and rodent studies that support the notion that the ability to recruit new fat cells through adipogenesis is a critical determinant of healthy adipose tissue distribution and remodeling in obesity. Furthermore, we discuss recent advances in our understanding of the identity of tissue-resident progenitor populations in WAT made possible through single-cell RNA sequencing analysis. A better understanding of adipose stem cell biology and adipogenesis may lead to novel strategies to uncouple obesity from metabolic disease. Find the latest version: https://jci.me/129191/pdf REVIEW SERIES: MECHANISMS UNDERLYING THE METABOLIC SYNDROME The Journal of Clinical Investigation Series Editor: Philipp E. Scherer Contribution of adipogenesis to healthy adipose tissue expansion in obesity Lavanya Vishvanath and Rana K. Gupta Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. The manner in which white adipose tissue (WAT) expands and remodels directly impacts the risk of developing metabolic syndrome in obesity. Preferential accumulation of visceral WAT is associated with increased risk for insulin resistance, whereas subcutaneous WAT expansion is protective. Moreover, pathologic WAT remodeling, typically characterized by adipocyte hypertrophy, chronic inflammation, and fibrosis, is associated with insulin resistance. Healthy WAT expansion, observed in the “metabolically healthy” obese, is generally associated with the presence of smaller and more numerous adipocytes, along with lower degrees of inflammation and fibrosis. Here, we highlight recent human and rodent studies that support the notion that the ability to recruit new fat cells through adipogenesis is a critical determinant of healthy adipose tissue distribution and remodeling in obesity. Furthermore, we discuss recent advances in our understanding of the identity of tissue-resident progenitor populations in WAT made possible through single-cell RNA sequencing analysis. A better understanding of adipose stem cell biology and adipogenesis may lead to novel strategies to uncouple obesity from metabolic disease. White adipose tissue as the principal site for a key enzyme in triglyceride synthesis, are associated with the energy storage development of one type of CGL. Familial partial lipodystrophy Proper control of nutrient homeostasis depends on safe and effi- (FPL) is a genetic disorder characterized by variable loss of body cient energy storage. In mammals, long-term energy storage is fat from the extremities and/or truncal region occurring in child- achieved through production of intracellular triglycerides, stored hood or puberty. Acquired lipodystrophies also occur, including within specialized cells called white adipocytes. White adipocytes the loss of subcutaneous fat observed in individuals taking prote- are capable of synthesizing triglycerides for long-term storage ase inhibitors for treatment of HIV (8, 9). During lipodystrophy, and liberating free fatty acids from triglycerides in times of ener- fatty acids overflow into nonadipose tissues (steatosis), including gy demand. Beyond their role as an energy bank, adipocytes are skeletal muscle, heart, pancreas, and liver. Ectopic lipid deposi- also active endocrine cells. Adipocyte secretory products (“adi- tion is deleterious, as accumulated lipid species (e.g., ceramides pokines”), such as leptin and adiponectin, regulate organismal and diacylglycerols) can interfere with insulin signaling and other energy homeostasis (1–3). tissue functions (termed lipotoxicity) (10–12). Hepatic steatosis, White adipocytes are found throughout the body and are gen- hypertriglyceridemia, and insulin resistance/diabetes all occur erally organized into anatomically distinct “depots.” Most white early in individuals with lipodystrophy (Figure 1). Leptin, owing to adipose tissue (WAT) depots are broadly characterized as either its ability to enhance lipid metabolism, is an effective treatment intra-abdominal or subcutaneous (4). WAT’s precise develop- for managing metabolic abnormalities in lipodystrophic patients mental origin during fetal development is still unclear; howev- (13). As such, both the energy-storing capacity and endocrine er, lineage tracing studies in mice indicate that subcutaneous functions of white adipocytes play a critical role in controlling and intra-abdominal depots emanate from distinct lineages (5). energy homeostasis. Human WAT expands from birth through adolescence via the Studies of WAT development have largely focused on under- expansion of cell size and number (6, 7). In adulthood, adipocytes standing the cellular basis of adipocyte differentiation, termed turn over at a rate of 10% per year, and adipocyte number remains adipogenesis. The nuclear hormone receptor PPARγ is a bona fide relatively stable regardless of BMI or weight loss (6). master regulator of adipocyte differentiation. PPARG is expressed WAT’s importance is quite clear from individuals or animal in committed adipocyte precursor cells (APCs), or “preadipo- models lacking functional adipose tissue (termed lipodystrophy). cytes,” and is further activated upon differentiation into adipo- Lipodystrophy results from impaired adipocyte development or cytes. PPARγ is essential for the differentiation of all adipocytes: inability to synthesize triglyceride (8). Congenital generalized humans with FPL and engineered mouse strains lacking function- lipodystrophy (CGL) is a rare autosomal-recessive disorder usu- al PPARG are severely lipodystrophic and insulin resistant (14, 15). ally recognized in neonates. Inactivating mutations in AGPAT2, Moreover, in vitro, PPARγ can drive adipocyte differentiation from fibroblasts or cells of mesenchymal origin (16). Great progress has been made in understanding the transcriptional mechanisms con- Conflict of interest: The authors have declared that no conflict of interest exists. trolling adipogenesis (17–19); however, the physiological mecha- Copyright: © 2019, American Society for Clinical Investigation. Reference information: J Clin Invest. 2019;129(10):4022–4031. nisms regulating adipocyte number in adulthood are less clear. In https://doi.org/10.1172/JCI129191. particular, the identity of APCs and the importance of adipogene- 4022 jci.org Volume 129 Number 10 October 2019 The Journal of Clinical Investigation REVIEW SERIES: MECHANISMS UNDERLYING THE METABOLIC SYNDROME Figure 1. Inadequate energy storage in adipose tissue underlies insulin resistance. Left: Lipodystrophy is characterized by an absolute or partial adipocyte deficiency, triggered by impaired adipocyte differentiation or triglyceride synthesis. This leads to ectopic lipid accumula- tion in other tissues, including the liver, skeletal muscle, heart, and pancreas. Toxic accumulation of lipid intermediates within these tissues leads to the development of insulin resistance. Middle: Pathologic obesity is often characterized by a relative adipocyte deficiency: limited expandabil- ity of the subcutaneous fat tissue, preferential expansion of visceral adipose tissue depots, and unhealthy adipose tissue remodeling (inflam- mation, fibrosis, limited adipogenesis). This is associated with ectopic lipid accumulation and insulin resistance, similar to what is observed in the lipodystrophy. Right: Metabolically healthy obesity is characterized by adequate expansion of protective subcutaneous depots, healthy adi- pose tissue remodeling (adipocyte hyperplasia), and limited ectopic lipid deposition. sis in adulthood are still being defined. Here, we highlight recent visceral WAT depots are intrinsically distinct “mini-organs,” and studies suggesting that the ability to recruit new fat cells through that developmental, functional, and molecular differences may adipogenesis is a critical determinant of both healthy adipose tis- underlie their differential contributions to nutrient homeostasis sue expansion and metabolic health in the setting of overnutrition. (30). Several studies using either rodent or human adipocytes col- We summarize recent single-cell sequencing efforts that have sub- lectively demonstrate that anatomically distinct adipocytes, in iso- stantially advanced our understanding of adipose tissue–resident lation, are functionally unique, differing in their ability to undergo progenitor identity and the potential for APC heterogeneity. A lipolysis and lipogenesis and activate thermogenic programs (23, better understanding of adipose stem cells and adipogenesis may 31–33). Further complicating matters, adipocyte heterogeneity lead to novel strategies to improve metabolic health in obesity. within individual