Switching harmful visceral fat to beneficial energy combustion improves metabolic dysfunctions

Yang, Xiaoyan; Sui, Wenhai; Dong, Mei; Lim, Sharon; Seki, Takahiro; Guo, Ziheng; Fischer, Carina; Lu, Huixia; Zhang, Cheng; Yang, Jianmin; Zhang, Meng; Wang, Yangang; Cao, Caixia; Gao, Yanbin; Zhao, Xinze; Sun, Meili; Sun, Yun; Zhuang, Rujie; Samani, Nilesh J.; Zhang, Yun; Cao, Yihai

doi:10.1172/jci.insight.89044

Cited by 27 publications

(22 citation statements)

References 35 publications

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“…Similar gene regulation, involved in thermogenic response and mitochondrial oxidation, was found in rats treated with Lep -expressing adenovirus (Zhou, Wang, Higa, Newgard & Unger 1999). Cao and co-workers proposed that this gene regulation can effectively reduce iAb fat depots (Yang, Sui, Zhang, Dong, Lim, Seki, Guo, Fischer, Lu, Zhang et al 2017). Both studies are in agreement with the proposed function of EREG as an upstream regulator of LEP secretion.…”

Section: Discussionmentioning

confidence: 99%

Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

Yasmeen

Shen

Lee

et al. 2018

Journal of Endocrinology

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Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis, and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal, white adipose tissue (iAb WAT) explants, as well as in vivo, in wild type mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG treated group compared to the control DIO group. EREG treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle, and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs. control DIO mice. All metabolic and gene regulation effects of EREG-treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.

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Section: Discussionmentioning

confidence: 99%

Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

Yasmeen

Shen

Lee

et al. 2018

Journal of Endocrinology

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“…Considering the browning ability differences, do adipose depots contribute to CAC differently? It has been reported that visceral fat may switch its phenotype for browning under certain stimulations (Yang et al, 2017), though the switching mechanism is still not well understood. This interesting question warrants further investigation and may improve our understanding of the mechanism of browning-conferred CAC.…”

Section: Browning In Cacmentioning

confidence: 99%

Fat Wasting Is Damaging: Role of Adipose Tissue in Cancer-Associated Cachexia

Sun

Feng

et al. 2020

Front. Cell Dev. Biol.

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Loss of body weight, especially loss of adipose tissue and skeletal muscle weight, characterizes cancer-associated cachexia (CAC). Clinically, therapeutic options for CAC are limited due to the complicated signaling between cancer and other organs. Recent research advances show that adipose tissues play a critical role during thermogenesis, glucose homeostasis, insulin sensitivity, and lipid metabolism. Understanding the adipocyte lipolysis, the formation of beige adipocytes, and the activation of brown adipocytes is vital for novel therapies for metabolic syndromes like CAC. The systemlevel crosstalk between adipose tissue and other organs involves adipocyte lipolysis, white adipose tissue browning, and secreted factors and metabolites. Novel CAC animal models and accumulating molecular signaling knowledge have provided mechanisms that may ultimately be translated into future therapeutic possibilities that benefit CAC patients. This mini review discusses the role of adipose tissue in CAC development, mechanism, and therapy.

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“…In the present study, because the total VAT mass was ~3.0-fold higher than the SAT mass, the improvement of VAT function, such as increased WAT browning, could explain the improvement of whole body glucose metabolism in diabetic GK rats after IT surgery. Similarly, it was reported by Yang et al that browning of VAT could improve global glucose and lipid metabolism, insulin sensitivity and hepatic steatosis in HFD-induced obese mice (Yang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 56%

Ileal Transposition Surgery Decreases Fat Mass and Improves Glucose Metabolism in Diabetic GK Rats: Possible Involvement of FGF21

et al. 2018

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Objective: Ileal transposition (IT) surgery has been reported to improve glucose and lipid metabolism, and fibroblast growth factor 21 (FGF21) is a powerful metabolic regulator. In the present study, we aimed to investigate the effects of IT surgery on metabolism and its possible relationship with the FGF21 signaling pathway in diabetic Goto-Kakizaki (GK) rats.Methods: Ten-week-old male GK rats were subjected to IT surgery with translocation of a 10 cm ileal segment to the proximal jejunum (IT group) or sham surgery without the ileum transposition (Sham-IT group). Rats in the no surgery group did not receive any surgical intervention. Six weeks later, body weight, fat mass, fasting blood glucose (FBG), and serum levels of FGF21 and leptin were measured. The expression of the FGF21 signaling pathway and white adipose tissue (WAT) browning-related genes in the WAT and liver were evaluated by real-time reverse transcription polymerase chain reaction (RT-qPCR) and western blot.Results: IT surgery significantly decreased the body weights and FBG levels and increased the insulin sensitivity of GK rats. The total WAT mass of the IT rats showed a 41.5% reduction compared with the Sham-IT rats, and serum levels of FGF21 and leptin of the IT rats decreased by 26.3 and 61.7%, respectively (all P < 0.05). The mRNA levels of fibroblast growth factor receptor 1 (FGFR1) and its co-receptor β klotho (KLB) in the perirenal WAT (pWAT) of the IT rats were 1.4- and 2.4-fold that of the Sham-IT rats, respectively, and the FGFR1 protein levels were 1.7-fold of the Sham-IT rats (all P < 0.05). In accordance with the pWAT, the protein levels of FGFR1 and KLB in the epididymal WAT (eWAT) of the IT rats notably increased to 3.0- and 3.9-fold of the Sham-IT rats (P < 0.05). Furthermore, uncoupling protein 1 (UCP1) protein levels in the eWAT and pWAT of the IT rats also increased to 2.2- and 2.3-fold of the Sham-IT rats (P < 0.05). However, the protein levels of FGFR1 and KLB in the subcutaneous WAT (sWAT) of the IT rats decreased by 34.4 and 72.1%, respectively, compared with the Sham-IT rats (P < 0.05). In addition, the protein levels of FGF21 and KLB in the livers of IT rats were 3.9- and 2.3-fold of the Sham-IT rats (all P < 0.05).Conclusions: IT surgery significantly decreased fat mass and improved glucose metabolism in diabetic GK rats. These beneficial roles of IT surgery were probably associated with its stimulatory action on the expression of FGFR1 and KLB in both the eWAT and the pWAT, thereby promoting UCP1 expression in these tissues.

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Switching harmful visceral fat to beneficial energy combustion improves metabolic dysfunctions

Cited by 27 publications

References 35 publications

Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

Fat Wasting Is Damaging: Role of Adipose Tissue in Cancer-Associated Cachexia

Ileal Transposition Surgery Decreases Fat Mass and Improves Glucose Metabolism in Diabetic GK Rats: Possible Involvement of FGF21

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