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

Paschoal, Vivian A.; Belchior, Thiago; Amano, Mariane Tami; Burgos-Silva, Marina; Peixoto, Álbert Souza; Magdalon, Juliana; Vieira, Thayna S.; Andrade, Mauro Figueiredo Carvalho de; Moreno, Mayara Franzoi; Chimin, Patrícia; Câmara, Niels Olsen Saraiva; Festuccia, William T.

doi:10.1002/mnfr.201800283

Cited by 7 publications

(11 citation statements)

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“…Mice were adapted to the metabolic cages for 2 consecutive days and evaluated for oxygen consumption (VO 2 ), carbon dioxide production (CO 2 ), spontaneous motor activity, and respiratory exchange ratio (RER, VCO 2 /VO 2 ratio) during 24 h in a Comprehensive Laboratory Monitoring System calorimeter (Columbus Instruments) as previously described …”

Section: Methodsmentioning

confidence: 99%

Fish Oil Protects Wild Type and Uncoupling Protein 1‐Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure

Oliveira

Castro

Belchior

et al. 2019

Molecular Nutrition Food Res

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Scope: The mechanisms and involvement of uncoupling protein 1 (UCP1) in the protection from obesity and insulin resistance induced by intake of a high-fat diet rich in omega-3 (n-3) fatty acids are investigated. Methods and results: C57BL/6J mice are fed either a low-fat (control group) or one of two isocaloric high-fat diets containing either lard (HFD) or fish oil (HFN3) as fat source and evaluated for body weight, adiposity, energy expenditure, glucose homeostasis, and inguinal white and interscapular brown adipose tissue (iWAT and iBAT, respectively) gene expression, lipidome, and mitochondrial bioenergetics. HFN3 intake protected from obesity, glucose and insulin intolerances, and hyperinsulinemia. This is associated with increased energy expenditure, iWAT UCP1 expression, and incorporation of n-3 eicosapentaenoic and docosahexaenoic fatty acids in iWAT and iBAT triacylglycerol. Importantly, HFN3 is equally effective in reducing body weight gain, adiposity, and glucose intolerance and increasing energy expenditure in wild-type and UCP1-deficient mice without recruiting other thermogenic processes in iWAT and iBAT, such as mitochondrial uncoupling and SERCA-mediated calcium and creatine-driven substrate cyclings. Conclusion: Intake of a high-fat diet rich in omega-3 fatty acids protects both wild-type and UCP1-deficient mice from obesity and insulin resistance by increasing energy expenditure through unknown mechanisms.

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Section: Methodsmentioning

confidence: 99%

Fish Oil Protects Wild Type and Uncoupling Protein 1‐Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure

Oliveira

Castro

Belchior

et al. 2019

Molecular Nutrition Food Res

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“…Constitutive mTORC1 activation in myeloid cells inhibits developing high-fat diet-induced obesity by promoting macrophage polarization to M2. Additionally, TSC1 deletion increases M2 macrophage polarization together with the mRNA levels of fatty acidbinding protein 4 and PPARγ, in an mTORC1-dependent manner (Paschoal et al 2018). Adipocyte-specific TSC1 deletion reduces visceral fat mass, as well as adipocyte number and diameter associated with increased lipolysis.…”

Section: Figurementioning

confidence: 95%

The effect of adipocyte–macrophage crosstalk in obesity-related breast cancer

Engin

Gönül

2019

Journal of Molecular Endocrinology

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Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid and tumor necrosis factor-α involve in a vicious cycle between adipocytes and macrophages aggravating inflammatory changes. Thereby, M1 macrophages form a characteristic ‘crown-like structure (CLS)’ around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity and aggressive behavior of breast cancer cells. Interlinked molecular mechanisms between adipocyte–macrophage–breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1–TSC2 complex–mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R)-positive postmenopausal breast cancer growth in obesity, adipocyte–macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin and insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin–estrogen–macrophage axis, and sirtuin 1 (SIRT1)–adipose-resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.

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“…The mechanisms by which rapamycin induces those metabolic complications and promotes inflammation are still unknown. Several pieces of evidence indicate that mTORC1 is an important positive regulator of PPARγ transcriptional activity in adipocytes [ 42,44,49 ] and macrophages [ 50 ] raising the possibility that some of the aforementioned metabolic complications associated with rapamycin treatment are due to inhibition of this transcription factor. PPARγ is a nuclear receptor expressed in adipocytes and macrophages, among other cells, that regulates glucose and lipid metabolism and inflammatory status.…”

Section: Introductionmentioning

confidence: 99%

“…Similar to adipocytes, myeloid cell Tsc1 deletion and therefore constitutive mTORC1 activation also protects mice from high‐fat diet‐induced obesity, white adipose tissue inflammation, and glucose intolerance by promoting an autonomous macrophage polarization to the alternative pro‐resolution M2 profile. [ 50 ] Mechanistically, enhanced M2 macrophage polarization induced by Tsc1 deletion is associated with increased PPARγ activity and oxidative metabolism. [ 50 ] Corroborating these findings, a recent study found that activation of the canonical Akt‐mTORC1 signaling pathway is a cardinal event in the macrophage polarization to M2 profile induced by IL‐4, through a mechanism involving ATP‐citrate lyase activation, histone acetylation and expression of a subset of M2‐related genes.…”

Section: Introductionmentioning

confidence: 99%

“…[ 50 ] Mechanistically, enhanced M2 macrophage polarization induced by Tsc1 deletion is associated with increased PPARγ activity and oxidative metabolism. [ 50 ] Corroborating these findings, a recent study found that activation of the canonical Akt‐mTORC1 signaling pathway is a cardinal event in the macrophage polarization to M2 profile induced by IL‐4, through a mechanism involving ATP‐citrate lyase activation, histone acetylation and expression of a subset of M2‐related genes. [ 28 ] Furthermore, Tsc1 deletion and therefore mTORC1 in human monocytes, murine myeloid cells and embryonic fibroblasts was also associated with 1) attenuation of the inflammatory response induced by LPS and elevation of IL‐10 production, [ 48 ] 2) lung and liver infiltration of alternatively activated M2 macrophages and reduction in iNOS expression, [ 71 ] and 3) activation of the energy sensor AMPK that promotes oxidative metabolism and resolution of inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases

Festuccia

2020

Molecular Nutrition Food Res

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ScopeEvidence gathered in the last decades suggests that lipotoxicity and inflammation are the main factors connecting adipose tissue dysfunction to the development of metabolic diseases such as insulin resistance, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and certain types of cancer, among others. The mechanistic target of rapamycin (mTOR) is a serine threonine kinase that functions as the catalytic entity of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). These complexes are important components of signaling pathways activated by nutrients, growth factors, and inflammatory mediators and are therefore directly involved in the regulation of adipocyte and macrophage metabolism and function.Methods and ResultsIn this article, studies that evaluate the involvement of mTORC1 and 2 in the regulation of macrophage and adipocyte function and their implication in the development of metabolic‐disease‐associated adipose tissue dysfunction are reviewed.ConclusionIn adipocytes, optimal levels of mTORC1 activity are required for its pro‐lipogenic actions, while in macrophages, mTORC1 regulates features of both M1 and M2 polarization. mTORC2, on the other hand, promotes glucose uptake and de novo lipogenesis in adipocytes and counteracts macrophage inflammatory response.

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

Abstract: 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.

Cited by 7 publications

References 48 publications

Fish Oil Protects Wild Type and Uncoupling Protein 1‐Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure

Fish Oil Protects Wild Type and Uncoupling Protein 1‐Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure

The effect of adipocyte–macrophage crosstalk in obesity-related breast cancer

Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases

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