Liraglutide induces beige fat development and promotes mitochondrial function in diet induced obesity mice partially through AMPK-SIRT-1-PGC1-α cell signaling pathway

Zhou, Jin-Jian; Poudel, Anil; Chandramani-Shivalingappa, Prashanth; Xu, Biao; Welchko, Ryan; Li, Lixin

doi:10.1007/s12020-018-1826-7

Cited by 37 publications

(23 citation statements)

References 55 publications

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“…SIRT1 and AMPK play important roles in the regulation of mitochondrial metabolism [39]. In this study, D3G significantly upregulated SIRT1 expression, which is a finding supported by previous research.…”

Section: Discussionsupporting

confidence: 89%

Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

2019

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Delphinidin-3-O-β-glucoside (D3G) is a health-promoting anthocyanin whose anti-obesity activity has not yet been thoroughly investigated. We examined the effects of D3G on adipogenesis and lipogenesis in 3T3-L1 adipocytes and primary white adipocytes using real-time RT-PCR and immunoblot analysis. D3G significantly inhibited the accumulation of lipids in a dose-dependent manner without displaying cytotoxicity. In the 3T3-L1 adipocytes, D3G downregulated the expression of key adipogenic and lipogenic markers, which are known as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor 1 (SREBP1), CCAAT/enhancer-binding protein alpha (C/EBPα), and fatty acid synthase (FAS). Moreover, the relative protein expression of silent mating type information regulation 2 homolog 1 (SIRT1) and carnitine palmitoyltransferase-1 (CPT-1) were increased, alongside reduced lipid levels and the presence of several small lipid droplets. Furthermore, D3G increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which suggests that D3G may play a role in AMPK and ACC activation in adipocytes. Our data indicate that D3G attenuates adipogenesis and promotes lipid metabolism by activating AMPK-mediated signaling, and, hence, could have a therapeutic role in the management and treatment of obesity.

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Section: Discussionsupporting

confidence: 89%

Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

2019

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“…BA also stimulates intestinal Lcell TGR5 to secrete glucagon-like peptide-1 (GLP-1). Although GLP-1 is known as an incretin to stimulate insulin secretion, it activates BAT thermogenesis and induces beige fat development through the action on its receptor in the hypothalamus (85) and the AMPK-SIRT-1-PGC1-α (AMP-activated protein kinasesirtuin 1-peroxisome proliferator-activated receptor gamma coactivator 1-alpha) cell signaling pathway (86). Crucial roles of TGR5 were also demonstrated in browning of white adipose tissue under multiple environmental cues including cold exposure and prolonged high-fat diet feeding (87).…”

Section: Mechanisms Of Dit: Gut Hormones and Bile Acidsmentioning

confidence: 99%

Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men

et al. 2020

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Since the recent rediscovery of brown adipose tissue (BAT) in adult humans, this thermogenic tissue has been attracting increasing interest. The inverse relationship between BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. Cold exposure activates and recruits BAT, resulting in increased energy expenditure and decreased body fatness. The stimulatory effects of cold exposure are mediated through transient receptor potential (TRP) channels and the sympathetic nervous system (SNS). Most TRP members also function as chemesthetic receptors for various food ingredients, and indeed, agonists of TRP vanilloid 1 such as capsaicin and its analog capsinoids mimic the effects of cold exposure to decrease body fatness through the activation and recruitment of BAT. The antiobesity effect of other food ingredients including tea catechins may be attributable, at least in part, to the activation of the TRP-SNS-BAT axis. BAT is also involved in the facultative thermogenesis induced by meal intake, referred to as diet-induced thermogenesis (DIT), which is a significant component of the total energy expenditure in our daily lives. Emerging evidence suggests a crucial role for the SNS in BAT-associated DIT, particularly during the early phase, but several gut-derived humoral factors may also participate in meal-induced BAT activation. One intriguing factor is bile acids, which activate BAT directly through Takeda G-protein receptor 5 (TGR5) in brown adipocytes. Given the apparent beneficial effects of some TRP agonists and bile acids on whole-body substrate and energy metabolism, the TRP/TGR5-BAT axis represents a promising target for combating obesity and related metabolic disorders in humans.

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“…Although this suggested improved insulin sensitivity upon Myrcludex B treatment, the responses to glucose and insulin tolerance tests were not different between HFD-fed Oatp1a/1b KO mice receiving placebo or Myrcludex B treatment ( Figure 1 D and E ). As it was recently shown that GLP-1 signaling can increase thermogenesis in brown adipose tissue (BAT), 24 , 25 , 26 , 27 we assessed body temperature using temperature transponders placed near the BAT. Body temperature in HFD-fed OATP1a/1b KO mice treated with Myrcludex B significantly increased with an average of 0.9°C, while body temperature of placebo-treated animals remained unchanged ( Figure 1 F ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity

Donkers

Abbing

Weeghel

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Bile acids are important metabolic signaling molecules. Bile acid receptor activation promotes body weight loss and improves glycemic control. The incretin hormone GLP-1 and thyroid hormone activation of T4 to T3 have been suggested as important contributors. Here, we identify the hepatic bile acid uptake transporter Na + taurocholate co-transporting polypeptide (NTCP) as target to prolong postprandial bile acid signaling. Methods Organic anion transporting polypeptide (OATP)1a/1b KO mice with or without reconstitution with human OATP1B1 in the liver were treated with the NTCP inhibitor Myrcludex B for 3.5 weeks after the onset of obesity induced by high fat diet-feeding. Furthermore, radiolabeled T4 was injected to determine the role of NTCP and OATPs in thyroid hormone clearance from plasma. Results Inhibition of NTCP by Myrcludex B in obese Oatp1a/1b KO mice inhibited hepatic clearance of bile acids from portal and systemic blood, stimulated GLP-1 secretion, reduced body weight, and decreased (hepatic) adiposity. NTCP inhibition did not affect hepatic T4 uptake nor lead to increased thyroid hormone activation. Myrcludex B treatment increased fecal energy output, explaining body weight reductions amongst unaltered food intake and energy expenditure. Conclusions Pharmacologically targeting hepatic bile acid uptake to increase bile acid signaling is a novel approach to treat obesity and induce GLP1- secretion.

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Liraglutide induces beige fat development and promotes mitochondrial function in diet induced obesity mice partially through AMPK-SIRT-1-PGC1-α cell signaling pathway

Cited by 37 publications

References 55 publications

Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity

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