Pten Positively Regulates Brown Adipose Function, Energy Expenditure, and Longevity

Ortega-Molina, Ana; Efeyan, Alejo; Lopez-Guadamillas, Elena; Muñoz‐Martín, Maribel; Gómez‐López, Gonzalo; Cañamero, Marta; Mulero, Francisca; Pastor, Joaquı́n; Martı́nez, Sonia; Romanos, Eduardo; Barroso, Gérard; Rial, Eduardo; Valverde, Ángela M.; Bischoff, James R.; Serrano, Manuel

doi:10.1016/j.cmet.2012.02.001

Cited by 310 publications

(305 citation statements)

References 69 publications

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“…Phosphatase and tensin homolog (PTEN) has also been reported to be a functional target gene of miR-382 (42); PTEN increases brown adipose function and energy expenditure (43). We observed increases in PTEN protein levels in the adipose tissue of BLC-supplemented mice (Fig.…”

Section: Discussionsupporting

confidence: 50%

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

et al. 2016

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There has been great interest in the browning of fat for the treatment of obesity. Although b-lapachone (BLC) has potential therapeutic effects on obesity, the fat-browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in mice fed a high-fat diet. Consistently, BLC-treated mice showed significantly higher energy expenditure compared with control mice. In vitro, BLC increased the expression of brown adipocyte-specific genes in stromal vascular fraction-differentiated adipocytes. BLC also controlled the expression of miR-382, which led to the upregulation of its direct target, Dio2. Upregulation of miR-382 markedly inhibited the differentiation of adipocytes into beige adipocytes, whereas BLC recovered beige adipocyte differentiation and increased the expression of Dio2 and UCP1. Our findings suggest that the BLC-mediated increase in the browning of WAT and the thermogenic capacity of BAT significantly results in increases in energy expenditure. Browning of WAT by BLC was partially controlled via the regulation of miR-382 targeting Dio2 and may lead to the prevention of diet-induced obesity.

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Section: Discussionsupporting

confidence: 50%

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

et al. 2016

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“…In addition to our study, PTEN overexpression in transgenic mice was recently shown to induce increased energy expenditure, hyperactive brown adipose tissues and reduced body fat accumulation [11,12]. It is therefore clear that chronic alterations of PTEN signalling in peripheral organs are correlated with adipose tissue plasticity.…”

Section: Discussionmentioning

confidence: 96%

“…Indeed, PTEN heterozygosity and PTEN tissue-specific deletions in muscle or adipose tissue all lead to improved glucose tolerance in healthy or obese/diabetic mice [8][9][10]. However, adding to the complexity of PTEN function, transgenic mice, overexpressing PTEN, display increased energy expenditure and insulin sensitivity [11,12]. Regarding the liver, we previously reported that PTEN is downregulated in steatotic livers of obese patients, as well as in rat models of genetic or diet-induced obesity [13].…”

Section: Introductionmentioning

confidence: 99%

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

Peyrou

Bourgoin

Poher

et al. 2015

Journal of Hepatology

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Background & Aims: PTEN is a dual lipid/protein phosphatase, downregulated in steatotic livers with obesity or HCV infection. Liver-specific PTEN knockout (LPTEN KO) mice develop steatosis, inflammation/fibrosis and hepatocellular carcinoma with aging, but surprisingly also enhanced glucose tolerance. This study aimed at understanding the mechanisms by which hepatic PTEN deficiency improves glucose tolerance, while promoting fatty liver diseases. Methods: Control and LPTEN KO mice underwent glucose/pyruvate tolerance tests and euglycemic-hyperinsulinemic clamps. Body fat distribution was assessed by EchoMRI, CT-scan and dissection analyses. Primary/cultured hepatocytes and insulin-sensitive tissues were analysed ex vivo. Results: PTEN deficiency in hepatocytes led to steatosis through increased fatty acid (FA) uptake and de novo lipogenesis. Although LPTEN KO mice exhibited hepatic steatosis, they displayed increased skeletal muscle insulin sensitivity and glucose uptake, as assessed by euglycemic-hyperinsulinemic clamps. Surprisingly, white adipose tissue (WAT) depots were also drastically reduced. Analyses of key enzymes involved in lipid metabolism further indicated that FA synthesis/esterification was decreased in WAT. In addition, Ucp1 expression and multilocular lipid droplet structures were observed in this tissue, indicating the presence of beige adipocytes. Consistent with a liver to muscle/ adipocyte crosstalk, the expression of liver-derived circulating factors, known to impact on muscle insulin sensitivity and WAT homeostasis (e.g. FGF21), was modulated in LPTEN KO mice.

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“…Indeed, lipid droplet content was lower (Fig. 3H-J), pointing to higher intracellular lipolysis (18).…”

Section: Salsalate Reverses Hfd-induced Obesity and Improves Glucose mentioning

confidence: 99%

Salsalate Activates Brown Adipose Tissue in Mice

et al. 2014

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Salsalate improves glucose intolerance and dyslipidemia in type 2 diabetes patients, but the mechanism is still unknown. The aim of the current study was to unravel the molecular mechanisms involved in these beneficial metabolic effects of salsalate by treating mice with salsalate during and after development of high-fat diet–induced obesity. We found that salsalate attenuated and reversed high-fat diet–induced weight gain, in particular fat mass accumulation, improved glucose tolerance, and lowered plasma triglyceride levels. Mechanistically, salsalate selectively promoted the uptake of fatty acids from glycerol tri[3H]oleate-labeled lipoprotein-like emulsion particles by brown adipose tissue (BAT), decreased the intracellular lipid content in BAT, and increased rectal temperature, all pointing to more active BAT. The treatment of differentiated T37i brown adipocytes with salsalate increased uncoupled respiration. Moreover, salsalate upregulated Ucp1 expression and enhanced glycerol release, a dual effect that was abolished by the inhibition of cAMP-dependent protein kinase (PKA). In conclusion, salsalate activates BAT, presumably by directly activating brown adipocytes via the PKA pathway, suggesting a novel mechanism that may explain its beneficial metabolic effects in type 2 diabetes patients.

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Pten Positively Regulates Brown Adipose Function, Energy Expenditure, and Longevity

Cited by 310 publications

References 69 publications

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

Salsalate Activates Brown Adipose Tissue in Mice

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