Developmental Origin of Fat: Tracking Obesity to Its Source

Gesta, Stéphane; Tseng, Yu–Hua; Kahn, C. Ronald

doi:10.1016/j.cell.2007.10.004

Cited by 1,269 publications

(893 citation statements)

References 104 publications

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“…Triacylglycerols stored in the white adipose tissue serve as the major energy reserve in higher eukaryotes (1). Although they are constantly turned over by lipolysis and re-esterification, their mobilization and storage are precisely balanced by various hormones and other factors depending on the nutritional state (2).…”

Section: Gpr109b Is Coupled To G I -Type G-proteins and Is Activated mentioning

confidence: 99%

Deorphanization of GPR109B as a Receptor for the β-Oxidation Intermediate 3-OH-octanoic Acid and Its Role in the Regulation of Lipolysis

Ahmed

Tunaru

Langhans

et al. 2009

Journal of Biological Chemistry

103

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The orphan G-protein-coupled receptor GPR109B is the result of a recent gene duplication of the nicotinic acid and ketone body receptor GPR109A being found in humans but not in rodents. Like GPR109A, GPR109B is predominantly expressed in adipocytes and is supposed to mediate antilipolytic effects. Here we show that GPR109B serves as a receptor for the ␤-oxidation intermediate 3-OH-octanoic acid, which has antilipolytic activity on human but not on murine adipocytes. GPR109B is coupled to G i -type G-proteins and is activated by 2-and 3-OH-octanoic acid with EC 50 values of about 4 and 8 M, respectively. Interestingly, 3-OH-octanoic acid plasma concentrations reach micromolar concentrations under conditions of increased ␤-oxidation rates, like in diabetic ketoacidosis or under a ketogenic diet. These data suggest that the ligand receptor pair 3-OH-octanoic acid/GPR109B mediates in humans a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in ␤-oxidation rates.

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Section: Gpr109b Is Coupled To G I -Type G-proteins and Is Activated mentioning

confidence: 99%

Deorphanization of GPR109B as a Receptor for the β-Oxidation Intermediate 3-OH-octanoic Acid and Its Role in the Regulation of Lipolysis

Ahmed

Tunaru

Langhans

et al. 2009

Journal of Biological Chemistry

103

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“…3 During the development of adipose tissue, pre-adipocytes or precursor/stem cells differentiate into mature adipocytes through complex adipogenic programs that regulate signaling transduction, transcriptional regulation, cell cycle and mitochondrial metabolism. [5][6][7][8][9][10] The transcription factor forkhead box O1 (FoxO1) regulates an array of genes and integrates insulin signaling with metabolic homeostasis, which has been shown to play an important role in adipogenesis. 5,[11][12][13][14][15] In particular, FoxO1 controls adipogenesis through interacting with peroxisome proliferator-activated receptor gamma (PPARg) and the cell cycle inhibitor p21 (CDKN1A).…”

Section: Introductionmentioning

confidence: 99%

Targeting FoxO1 with AS1842856 Suppresses Adipogenesis

et al. 2014

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Abbreviations: AS1842856, 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid BMI, basal media I; BMII, basal media II; C1, mitochondrial complex I; C3, mitochondrial complex III; DMI, differentiation media I; DMII, differentiation media II; FoxO1, forkhead box O1; G6P, glucose 6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; PPARg, peroxisome proliferator-activated receptor gamma; T2DM, type 2 diabetes mellitus.Hyperplasia (i.e., increased adipogenesis) contributes to excess adiposity, the hallmark of obesity that can trigger metabolic complications. As FoxO1 has been implicated in adipogenic regulation, we investigated the kinetics of FoxO1 activation during adipocyte differentiation, and tested the effects of FoxO1 antagonist (AS1842856) on adipogenesis. We found for the first time that the kinetics of FoxO1 activation follows a series of sigmoid curves, and reveals the phases relevant to clonal expansion, cell cycle arrest, and the regulation of PPARg, adiponectin, and mitochondrial proteins (complexes I and III). In addition, multiple activation-inactivation transitions exist in the stage of terminal differentiation. Importantly, persistent inhibition of FoxO1 with AS1842856 almost completely suppressed adipocyte differentiation, while selective inhibition in specific stages had differential effects on adipogenesis. Our data present a new view of FoxO1 in adipogenic regulation, and suggest AS1842856 can be an anti-obesity agent that warrants further investigation.

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“…7 Like muscle and bone, adipose tissue is mesodermal in origin. 9 In mice, adipose tissue development occurs during the first two weeks of neonatal life. 9,10 The observation that developmental exposure to testosterone programed WAT, muscle, and bone suggested a possible effect of testosterone on mesenchymal stem cells.…”

mentioning

confidence: 99%

“…9 In mice, adipose tissue development occurs during the first two weeks of neonatal life. 9,10 The observation that developmental exposure to testosterone programed WAT, muscle, and bone suggested a possible effect of testosterone on mesenchymal stem cells. Indeed, we observed that in NTF, expression of developmental genes involved in depot-specific identity was altered in SC adipose tissue.…”

mentioning

confidence: 99%

“…In humans and primates, synaptogenesis of hypothalamic centers controlling body adiposity and peripheral adipose tissue development occur during the second trimester of pregnancy. 9,10,19 Conversely, the mouse is an altricial species that gives birth to immature young. In mice, developmental plasticity of hypothalamic circuits controlling adiposity and peripheral adipose tissue development occur during the first two weeks of neonatal life.…”

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confidence: 99%

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