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MTOR complex 2 in adipose tissue negatively controls whole-body growth.

ABSTRACT: Mammalian target of rapamycin (mTOR), a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors, is found in 2 structurally and functionally distinct multiprotein complexes termed mTOR complex 1 (mTORC1) and mTORC2. mTORC2, which consists of rictor, mSIN1, mLST8, and mTOR, is activated by insulin/IGF1 and phosphorylates Ser-473 in the hydrophobic motif of Akt/PKB. Though the role of mTOR in single cells is relatively well characterized, the role of mTOR signaling in specific tissues and how this may contribute to overall body growth is poorly understood. To examine the role of mTORC2 in an individual tissue, we generated adipose-specific rictor knockout mice (rictor(ad-/-)). Rictor(ad-/-) mice are increased in body size due to an increase in size of nonadipose organs, including heart, kidney, spleen, and bone. Furthermore, rictor(ad-/-) mice have a disproportionately enlarged pancreas and are hyperinsulinemic, but glucose tolerant, and display elevated levels of insulin-like growth factor 1 (IGF1) and IGF1 binding protein 3 (IGFBP3). These effects are observed in mice on either a high-fat or a normal diet, but are generally more pronounced in mice on a high-fat diet. Our findings suggest that adipose tissue, in particular mTORC2 in adipose tissue, plays an unexpectedly central role in controlling whole-body growth.

SUBMITTER: Cybulski N

PROVIDER: S-EPMC2700987 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveFibroblast growth factor 21 (FGF21) has been shown to rapidly lower body weight in the Siberian hamster, a preclinical model of adiposity. This induced negative energy balance mediated by FGF21 is associated with both lowered caloric intake and increased energy expenditure. Previous research demonstrated that adipose tissue (AT) is one of the primary sites of FGF21 action and may be responsible for its ability to increase the whole-body metabolic rate. The present study sought to determine the relative importance of white (subcutaneous AT [sWAT] and visceral AT [vWAT]), and brown (interscapular brown AT [iBAT]) in governing FGF21-mediated metabolic improvements using the tissue-specific uptake of glucose and lipids as a proxy for metabolic activity.MethodsWe used positron emission tomography-computed tomography (PET-CT) imaging in combination with both glucose (18F-fluorodeoxyglucose) and lipid (18F-4-thiapalmitate) tracers to assess the effect of FGF21 on the tissue-specific uptake of these metabolites and compared responses to a control group pair-fed to match the food intake of the FGF21-treated group. In vivo imaging was combined with ex vivo tissue-specific functional, biochemical, and molecular analyses of the nutrient uptake and signaling pathways.ResultsConsistent with previous findings, FGF21 reduced body weight via reduced caloric intake and increased energy expenditure in the Siberian hamster. PET-CT studies demonstrated that FGF21 increased the uptake of glucose in BAT and WAT independently of reduced food intake and body weight as demonstrated by imaging of the pair-fed group. Furthermore, FGF21 increased glucose uptake in the primary adipocytes, confirming that these in vivo effects may be due to a direct action of FGF21 at the level of the adipocytes. Mechanistically, the effects of FGF21 are associated with activation of the ERK signaling pathway and upregulation of GLUT4 protein content in all fat depots. In response to treatment with FGF21, we observed an increase in the markers of lipolysis and lipogenesis in both the subcutaneous and visceral WAT depots. In contrast, FGF21 was only able to directly increase the uptake of lipid into BAT.ConclusionsThese data identify brown and white fat depots as primary peripheral sites of action of FGF21 in promoting glucose uptake and also indicate that FGF21 selectively stimulates lipid uptake in brown fat, which may fuel thermogenesis.

Project description:BackgroundThe conventional measurement of obesity utilises the body mass index (BMI) criterion. Although there are benefits to this method, there is concern that not all individuals at risk of obesity-associated medical conditions are being identified. Whole-body fat percentage (%FM), and specifically visceral adipose tissue (VAT) mass, are correlated with and potentially implicated in disease trajectories, but are not fully accounted for through BMI evaluation. The aims of this study were (a) to compare five anthropometric predictors of %FM and VAT mass, and (b) to explore new cut-points for the best of these predictors to improve the characterisation of obesity.MethodsBMI, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and waist/height0.5 (WHT.5R) were measured and calculated for 81 adults (40 women, 41 men; mean (SD) age: 38.4 (17.5) years; 94% Caucasian). Total body dual energy X-ray absorptiometry with Corescan (GE Lunar iDXA, Encore version 15.0) was also performed to quantify %FM and VAT mass. Linear regression analysis, stratified by sex, was applied to predict both %FM and VAT mass for each anthropometric variable. Within each sex, we used information theoretic methods (Akaike Information Criterion; AIC) to compare models. For the best anthropometric predictor, we derived tentative cut-points for classifying individuals as obese (>25% FM for men or >35% FM for women, or > highest tertile for VAT mass).ResultsThe best predictor of both %FM and VAT mass in men and women was WHtR. Derived cut-points for predicting whole body obesity were 0.53 in men and 0.54 in women. The cut-point for predicting visceral obesity was 0.59 in both sexes.ConclusionsIn the absence of more objective measures of central obesity and adiposity, WHtR is a suitable proxy measure in both women and men. The proposed DXA-%FM and VAT mass cut-offs require validation in larger studies, but offer potential for improvement of obesity characterisation and the identification of individuals who would most benefit from therapeutic intervention.

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MTOR complex 2 in adipose tissue negatively controls whole-body growth.

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