Thiago Belchior

Omega-3 fatty acids protect from diet-induced obesity, glucose intolerance, and adipose tissue inflammation through PPARγ-dependent and PPARγ-independent actions

SCOPE We tested herein the hypothesis that peroxisome proliferator activated receptor γ (PPARγ) is a major mediator of omega-3 (n-3) protective actions against high-fat diet (HFD) induced obesity, glucose intolerance, and adipose tissue inflammation. METHODS AND RESULTS C57BL6 wild-type and fat-1 transgenic (fat-1) mice were fed a low-fat diet (LFD) or HFD, treated or not with PPARγ antagonist, and evaluated for energy balance, adiposity, glucose tolerance, and adipose tissue inflammation. Fat-1 mice were protected from obesity, fasting hyperglycemia, glucose intolerance, and adipose tissue inflammation. PPARγ inhibition completely abolished fat-1 protection against HFD-induced glucose intolerance, but not obesity or adipose tissue inflammation. To investigate the role of myeloid cell as mediator of n-3 beneficial metabolic actions, mice with deletion (LyzM-PPARγ(KO)) or nondeletion (LyzM-PPARγ(WT)) of PPARγ in myeloid cells were fed either LFD or HFD (lard) or an HFD rich in n-3 (fish oil). Our findings indicate that myeloid cell associated PPARγ is not involved in the attenuation of HFD-induced glucose intolerance and adipose tissue inflammation induced by n-3. CONCLUSION High endogenous n-3 fatty acid levels protect from HFD obesity, glucose intolerance, and adipose tissue inflammation. Among these, only protection against glucose intolerance is mediated by non-myeloid cell PPARγ.

PPARγ activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats

mTOR inhibition with rapamycin induces a diabetes-like syndrome characterized by severe glucose intolerance, hyperinsulinemia, and hypertriglyceridemia, which is due to increased hepatic glucose production as well as reduced skeletal muscle glucose uptake and adipose tissue PPARγ activity. Herein, we tested the hypothesis that pharmacological PPARγ activation attenuates the diabetes-like syndrome associated with chronic mTOR inhibition. Rats treated with the mTOR inhibitor rapamycin (2 mg·kg(-1)·day(-1)) in combination or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1)) for 15 days were evaluated for insulin secretion, glucose, insulin, and pyruvate tolerance, skeletal muscle and adipose tissue glucose uptake, and insulin signaling. Rosiglitazone corrected fasting hyperglycemia, attenuated the glucose and insulin intolerances, and abolished the increase in fasting plasma insulin and C-peptide levels induced by rapamycin. Surprisingly, rosiglitazone markedly increased the plasma insulin and C-peptide responses to refeeding in rapamycin-treated rats. Furthermore, rosiglitazone partially attenuated rapamycin-induced gluconeogenesis, as evidenced by the improved pyruvate tolerance and reduced mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Rosiglitazone also restored insulins ability to stimulate glucose uptake and its incorporation into glycogen in skeletal muscle of rapamycin-treated rats, which was associated with normalization of Akt Ser(473) phosphorylation. However, the rapamycin-mediated impairments of adipose tissue glucose uptake and incorporation into triacylglycerol were unaffected by rosiglitazone. Our findings indicate that PPARγ activation ameliorates some of the disturbances in glucose homeostasis and insulin action associated with chronic rapamycin treatment by reducing gluconeogenesis and insulin secretion and restoring muscle insulin signaling and glucose uptake.

Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice

Mechanistic target of rapamycin complex 1 (mTORC1) loss of function reduces adiposity whereas partial mTORC1 inhibition enhances fat deposition. Herein we evaluated how constitutive mTORC1 activation in adipocytes modulates adiposity in vivo. Mice with constitutive mTORC1 activation in adipocytes induced by tuberous sclerosis complex (Tsc)1 deletion and littermate controls were evaluated for body mass, energy expenditure, glucose and fatty acid metabolism, mitochondrial function, mRNA and protein contents. Adipocyte-specific Tsc1 deletion reduced visceral, but not subcutaneous, fat mass, as well as adipocyte number and diameter, phenotypes that were associated with increased lipolysis, UCP-1 content (browning) and mRNA levels of pro-browning transcriptional factors C/EBPβ and ERRα. Adipocyte Tsc1 deletion enhanced mitochondrial oxidative activity, fatty acid oxidation and the expression of PGC-1α and PPARα in both visceral and subcutaneous fat. In brown adipocytes, however, Tsc1 deletion did not affect UCP-1 content and basal respiration. Adipocyte Tsc1 deletion also reduced visceral adiposity and enhanced glucose tolerance, liver and muscle insulin signaling and adiponectin secretion in mice fed with purified low- or high-fat diet. In conclusion, adipocyte-specific Tsc1 deletion enhances mitochondrial activity, induces browning and reduces visceral adiposity in mice.

mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function.

Genetic- and diet-induced obesity and insulin resistance are associated with an increase in mechanistic target of rapamycin complex (mTORC) 1 activity in adipose tissue. We investigated herein the effects of pharmacological mTORC1 inhibition in the development of adipose tissue inflammation induced by high-fat diet (HFD) feeding, as well as in the polarization, metabolism and function of bone marrow-derived macrophages (BMDM). For this, C57BL/6J mice fed with a standard chow diet or a HFD (60% of calories from fat) and treated with either vehicle (0.1% Me2SO, 0.2% methylcellulose) or rapamycin (2mg/kg/ day, gavage) during 30days were evaluated for body weight, adiposity, glucose tolerance and adipose tissue inflammation. Although rapamycin did not affect the increase in body weight and adiposity, it exacerbated the glucose intolerance and adipose tissue inflammation induced by HFD feeding, as evidenced by the increased adipose tissue percentage of M1 macrophages, naive and activated cytotoxic T lymphocytes, and mRNA levels of proinflammatory molecules, such as TNF-α, IL-6 and MCP-1. In BMDM in vitro, pharmacological mTORC1 inhibition induced phosphorylation of NFκB p65 and spontaneous polarization of macrophages to a proinflammatory M1 profile, while it impaired M2 polarization induced by IL-4+IL-13, glycolysis and phagocytosis. Altogether, these findings indicate that mTORC1 activity is an important determinant of adipose tissue inflammatory profile and macrophage plasticity, metabolism and function.

Cagaita fruit (Eugenia dysenterica DC.) and obesity: Role of polyphenols on already established obesity

Polyphenol-rich cagaita (Eugenia dysenterica DC.) extracts (PCE) have previously shown to prevent body weight and adiposity induced by high-fat/high-sucrose (HFS) diet. Whether PCE also exerts protective effects in already developed obesity is unknown. In order to test this hypothesis, male C57BL/6J obese mice (previously feed with a HFS diet for six weeks) were treated with PCE at two doses, 7mg gallic acid equivalent (GAE)/kg body weight (PCE I group), and 14mg GAE/kg body weight (PCE II group) or water (HFS and Chow groups) by oral gavage for eight weeks. PCE did not affect body weight and adiposity of obese mice. However, PCE did protect against dyslipidemia, fasting hyperglycemia, and glucose intolerance, and attenuated both hepatic gluconeogenesis and inflammation as observed by the expression of tumor necrosis factor-α and transcriptional factor NF-κB. These results indicate that PCE improves glucose homeostasis of obese mice by attenuating hepatic gluconeogenesis and inflammation.

Constitutive Activation of the Nutrient Sensor mTORC1 in Myeloid Cells Induced by Tsc1 Deletion Protects Mice from Diet‐Induced Obesity

SCOPE To test whether myeloid cells Tsc1 deletion and therefore constitutive activation of the nutrient sensor mTORC1 protects from high-fat diet (HFD)-induced obesity, glucose intolerance, and adipose tissue inflammation. METHODS AND RESULTS Mice with Tsc1 deletion in myeloid cells (MTsc1KO) and littermate controls (MTsc1WT) were fed with HFD for 8 weeks and evaluated for body weight, glucose homeostasis, and adipose tissue inflammation. MTsc1KO mice were protected from HFD-induced obesity and glucose intolerance. MTsc1KO, however, displayed, independently of the diet, abnormal behavior, episodes of intense movement, and muscle spasms followed by temporary paralysis. To investigate whether obesity protection was due to myeloid cells Tsc1 deletion, bone marrow was transplanted from MTsc1WT and MTsc1KO into irradiated C57BL6/J mice. Mice transplanted with MTsc1KO bone marrow displayed reduced body weight gain, adiposity, and inflammation, and enhanced energy expenditure, glucose tolerance and adipose tissue M2 macrophage content upon HFD feeding, in the absence of abnormal behavior. In vitro, Tsc1 deletion increased in a mTORC1-dependent manner macrophage polarization to M2 profile and mRNA levels of fatty acid binding protein 4 and PPARγ. CONCLUSION Constitutive mTORC1 activation in myeloid cells protects mice from HFD-induced obesity, adipose tissue inflammation, and glucose intolerance by promoting macrophage polarization to M2 pro-resolution profile and increasing energy expenditure.

Regulation of Metabolic Disease-Associated Inflammation by Nutrient Sensors

Visceral obesity is frequently associated with the development of type 2 diabetes (T2D), a highly prevalent chronic disease that features insulin resistance and pancreatic β-cell dysfunction as important hallmarks. Recent evidence indicates that the chronic, low-grade inflammation commonly associated with visceral obesity plays a major role connecting the excessive visceral fat deposition with the development of insulin resistance and pancreatic β-cell dysfunction. Herein, we review the mechanisms by which nutrients modulate obesity-associated inflammation.