White adipose (fat) tissues regulate metabolism, reproduction, and life span. Adipocytes form throughout life, with the most marked expansion of the lineage occurring during the postnatal period. Adipocytes develop in coordination with the vasculature, but the identity and location of white adipocyte progenitor cells in vivo are unknown. We used genetically marked mice to isolate proliferating and renewing adipogenic progenitors. We found that most adipocytes descend from a pool of these proliferating progenitors that are already committed, either prenatally or early in postnatal life. These progenitors reside in the mural cell compartment of the adipose vasculature, but not in the vasculature of other tissues. Thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development.

Fat-resident regulatory T cells (fTreg cells) accumulate in adipose tissue of mice as a function of age, but not obesity; mice without fTreg cells are protected against age-associated insulin resistance, but remain susceptible to obesity-associated insulin resistance and metabolic disease, indicating different aetiologies of age-associated versus obesity-associated insulin resistance. Age-associated insulin resistance (IR) and obesity-associated IR are physiologically distinct forms of adult-onset diabetes. Although macrophage-driven inflammation drives the obesity-associated condition, the mechanisms for age-associated IR are not known. Ronald Evans and colleagues show that fat-resident regulatory T cells (fTreg cells) accumulate in adipose tissue as a function of age, but not obesity. Mice lacking fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. Depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. Although not the main topic of this study, these findings do not support a role for fTreg cells in obesity-associated insulin resistance or in the therapeutic actions of thiazolidinedione or 'glitazone' antidiabetics. This contradicts claims that Treg cells were beneficial and necessary for restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR1,2,3,4,5,6, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR7 are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.

PPARγ induces fibroblast growth factor 1 to remodel visceral adipose tissue in response to a high-fat diet to maintain metabolic homeostasis. Fibroblast growth factor 1 (FGF1) and the other known FGF family proteins have been implicated in a range of physiological processes but, surprisingly, FGF1 knockout mice display no obvious abnormality. Here the authors show that FGF1 is induced in visceral adipose tissue in response to a high-fat diet. This induction of FGF1 in the fed state is regulated by the nuclear receptor PPARγ. Mice without FGF1 have an impaired metabolic response of visceral adipose in response to high-fat diet, and develop an aggressive diabetic phenotype coupled to aberrant adipose expansion. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as crucial for maintaining metabolic homeostasis and insulin sensitization. Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood1,2. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs3,4,5. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes6. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions7,8,9. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.