PPARγ is a major regulator of branched-chain amino acid blood levels and catabolism in white and brown adipose tissues

Blanchard, Pierre‐Gilles; Moreira, Roger William Fernandes; Castro, Érique; Caron, Alexandre; Côté, Marie‐Pier; Andrade, Mauro Figueiredo Carvalho de; Oliveira, Tiago E.; Ortiz‐Silva, Milene; Peixoto, Álbert Souza; Gélinas, Yves; Guerra‐Sá, Renata; Deshaies, Yves; Festuccia, William T.

doi:10.1016/j.metabol.2018.09.007

Cited by 33 publications

(26 citation statements)

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“…Reports have demonstrated metabolic effects of altered BCAA consumption in WAT and BAT (13)(14)(15)40), but to our knowledge, a direct comparison of WAT and BAT has not been performed. We found that, in C57BL/6 mice, BAT showed several-fold higher mRNA expression of key BCAA catabolic enzymes compared with WAT (e.g., Bckdha, Hibch, and Hibadh) (Fig.…”

Section: Bcaa Metabolism and 3-hib In White And Brown Adipocytesmentioning

confidence: 92%

“…Several studies have shown a strong association between insulin resistance and increased concentrations of circulating branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) (6,7), also after controlling for age, BMI, sex, and race, although particular associations were observed for nonobese people and males with type 2 diabetes (8). Elevation of these essential amino acids in obesity and insulin resistance reflects, at least partly, reduced BCAA catabolism in adipose tissue, involving decreased expression and/or activity of BCAA catabolic enzymes (9)(10)(11)(12)(13)(14)(15)(16)(17). People with obesity exhibit reduced catabolism of BCAAs in visceral and subcutaneous adipose tissue, which is normalized after bariatric surgery (18).…”

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confidence: 99%

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3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

et al. 2020

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Circulating branched-chain amino acids (BCAAs) associate with insulin resistance and type 2 diabetes. 3-Hydroxyisobutyrate (3-HIB) is a catabolic intermediate of the BCAA valine. In this study, we show that in a cohort of 4,942 men and women, circulating 3-HIB is elevated according to levels of hyperglycemia and established type 2 diabetes. In complementary cohorts with measures of insulin resistance, we found positive correlates for circulating 3-HIB concentrations with HOMA2 of insulin resistance, as well as a transient increase in 3-HIB followed by a marked decrease after bariatric surgery and weight loss. During differentiation, both white and brown adipocytes upregulate BCAA utilization and release increasing amounts of 3-HIB. Knockdown of the 3-HIB-forming enzyme 3-hydroxyisobutyryl-CoA hydrolase decreases release of 3-HIB and lipid accumulation in both cell types. Conversely, addition of 3-HIB to white and brown adipocyte cultures increases fatty acid uptake and modulated insulin-stimulated glucose uptake in a time-dependent manner. Finally, 3-HIB treatment decreases mitochondrial oxygen consumption and generation of reactive oxygen species in white adipocytes, while increasing these measures in brown adipocytes. Our data establish 3-HIB as a novel adipocyte-derived regulator of adipocyte subtypespecific functions strongly linked to obesity, insulin resistance, and type 2 diabetes.

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Section: Bcaa Metabolism and 3-hib In White And Brown Adipocytesmentioning

confidence: 92%

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confidence: 99%

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

et al. 2020

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“…PPAR‐γ is not only essential to preadipocyte differentiation into mature adipocytes, but also a critical regulator of adipocyte metabolic and endocrine functions . Indeed, either whole‐body or adipocyte‐specific PPAR‐γ deletion results in complete loss of adipose tissue (generalized lipodystrophy), hyperlipidemia, insulin resistance, and organomegaly …”

Section: Introductionmentioning

confidence: 99%

Lipoatrophy‐Associated Insulin Resistance and Hepatic Steatosis are Attenuated by Intake of Diet Rich in Omega 3 Fatty Acids

Moreira

Castro

Oliveira

et al. 2020

Molecular Nutrition Food Res

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Scope: Glucose homeostasis and progression of nonalcoholic fatty liver disease (NAFLD) and hepatomegaly in severe lipoatrophic mice and their modulation by intake of a diet rich in omega 3 (n-3) fatty acids (HFO) are evaluated. Methods and results: Severe lipoatrophic mice induced by PPAR-deletion exclusively in adipocytes (A-PPAR KO) and littermate controls (A-PPAR WT)are evaluated for glucose homeostasis and liver mass, proteomics, lipidomics, inflammation, and fibrosis. Lipoatrophic mice are heavier than controls, severely glucose intolerant, and hyperinsulinemic, and develop NAFLD characterized by increased liver glycogen, triacylglycerol, and diacylglycerol contents, mitotic index, apoptosis, inflammation, steatosis score, fibrosis, and fatty acid synthase (FAS) content and activity. Lipoatrophic mice also display liver enrichment with monounsaturated in detriment of polyunsaturated fatty acids including n-3 fatty acids, and increased content of cardiolipin, a tetracyl phospholipid exclusively found at the mitochondria inner membrane. Administration of a high-fat diet rich in n-3 fatty acids (HFO) to lipoatrophic mice enriches liver with n-3 fatty acids, reduces hepatic steatosis, FAS content and activity, apoptosis, inflammation, and improves glucose homeostasis. Conclusion: Diet enrichment with n-3 fatty acids improves glucose homeostasis and reduces liver steatosis and inflammation without affecting hepatomegaly in severe lipoatrophic mice.

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“…Several key factors in regulating BAT function have been identified such as peroxisome proliferator-activated receptor γ (PPARγ), PPARγ cofactor-1α (PGC-1α), and PR domain containing 16 (PRDM16) [7][8][9]. PPARγ, forming a heterodimer with retinoid X receptor (RXR), activates Ucp1 gene expression by binding to the peroxisome proliferator response element (PPRE) in the Ucp1 promoter [10].…”

Section: Introductionmentioning

confidence: 99%

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

Fang

et al. 2019

Metabolism

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The thermogenic brown adipose tissue (BAT) has been proposed as a potential target to prevent or treat obesity and related metabolic diseases. BAT secretes adipokines to regulate the thermogenic program in an autocrine or paracrine manner. Follistatin-like 1 (FSTL1), a glycoprotein involved in adipogenesis and obesity, however, the function of FSTL1 in BAT thermogenesis and in the regulation of systemic energy homeostasis are not fully understood. Methods: Whole-body ablation Fstl1 heterozygous mice (Fstl1 +/−) and its littermates control were injected with CL316,243 to assess energy balance. A series of FSTL1 overexpression and knockdown experiments were carried out to evaluate its function in regulating thermogenic gene expression in brown adipocytes. Results: FSTL1 expression was induced upon BAT activation during cold challenge or β3-adrenergic activation. FSTL1 haploinsufficiency in mice led to reduced thermogenic gene expression, impaired BAT recruitment, and decreased heat production. FSTL1 cell-autonomously promoted the β3-adrenergic signaling, which was required to upregulate PPARγ and UCP1 in brown adipocytes. Furthermore, only glycosylated FSTL1 could be secreted from brown adipocytes to induce the β3-adrenergic activation. Conclusions: Our results suggest FSTL1 as a novel stimulator of the β-adrenergic signaling and BAT thermogenesis.

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PPARγ is a major regulator of branched-chain amino acid blood levels and catabolism in white and brown adipose tissues

Cited by 33 publications

References 50 publications

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

Lipoatrophy‐Associated Insulin Resistance and Hepatic Steatosis are Attenuated by Intake of Diet Rich in Omega 3 Fatty Acids

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

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