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A PPAR?-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.

ABSTRACT: 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 understood. 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 PPAR? (peroxisome proliferator activated receptor ?), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. 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 changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. 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 PPAR? 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 PPAR?–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.

SUBMITTER: Jonker JW

PROVIDER: S-EPMC3358516 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.

Jonker Johan W JW Suh Jae Myoung JM Atkins Annette R AR Ahmadian Maryam M Li Pingping P Whyte Jamie J He Mingxiao M Juguilon Henry H Yin Yun-Qiang YQ Phillips Colin T CT Yu Ruth T RT Olefsky Jerrold M JM Henry Robert R RR Downes Michael M Evans Ronald M RM

Nature 20120501 7398

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 understood. 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 ...[more]

PMID: 22522926

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Project description:BackgroundEnergy-dissipating brown adipocytes have significant potential for improving systemic metabolism. Vanin-1, a membrane-bound pantetheinase, is involved in various biological processes in mice. However, its role in BAT mitochondrial function is still unclear. In this study, we aimed to elucidate the impact of Vanin-1 on BAT function and contribution during overnutrition-induced obesity.MethodsVanin-1 expression was analyzed in different adipose depots in mice. The cellular localization of Vanin-1 was analyzed by confocal microscopy and western blots. Mice lacking Vanin-1 (Vanin-1-/-) were continuously fed either a chow diet or a high-fat diet (HFD) to establish an obesity model. RNA-seq analysis was performed to identify the molecular changes associated with Vanin-1 deficiency during obesity. BAT-specific Vanin-1 overexpression mice were established to determine the effects of Vanin-1 in vivo. Cysteamine treatment was used to examine the effect of enzymatic reaction products of Vanin-1 on BAT mitochondria function in Vanin-1-/- mice.ResultsThe results indicate that the expression of Vanin-1 is reduced in BAT from both diet-induced and leptin-deficient obese mice. Study on the subcellular location of Vanin-1 shows that it has a mitochondrial localization. Vanin-1 deficiency results in increased adiposity, BAT dysfunction, aberrant mitochondrial structure, and promotes HFD induced-BAT whitening. This is attributed to the impairment of the electron transport chain (ETC) in mitochondria due to Vanin-1 deficiency, resulting in reduced mitochondrial respiration. Overexpression of Vanin-1 significantly enhances energy expenditure and thermogenesis in BAT, renders mice resistant to diet-induced obesity. Furthermore, treatment with cysteamine rescue the mitochondrial dysfunction in Vanin-1-/- mice.ConclusionsCollectively, these findings suggest that Vanin-1 plays a crucial role in promoting mitochondrial respiration to counteract diet-induced obesity, making it a potential therapeutic target for obesity.

Dataset Information

A PPAR?-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.

Publications

A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.

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