Dataset Information

Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

ABSTRACT: Transforming growth factor beta (TGF-β) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-β signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high-fat diet (HFD) in hepatocyte-specific TGF-β receptor II-deficient (Tgfbr2^ΔHEP ) and Tgfbr2^flox/flox mice. In addition, browning of white adipose tissue (WAT) was induced by administration of CL-316,243 (a β3-adrenergic agonist) or cold exposure for 7 days. Compared with Tgfbr2 ^flox/flox mice, Tgfbr2^ΔHEP mice were resistant to steatosis and obesity. The metabolic changes in Tgfbr2^ΔHEP mice were due to the increase of mitochondrial oxidative phosphorylation in the liver and white-to-beige fat conversion. A further mechanistic study revealed that exosomal let-7b-5p derived from hepatocytes was robustly elevated after stimulation with palmitic acid and TGF-β. Indeed, let-7b-5p levels were low in the liver, serum exosomes, inguinal WAT, and epididymal WAT in HFD-fed Tgfbr2^ΔHEP mice. Moreover, 3T3-L1 cells internalized hepatocyte-derived exosomes. An in vitro experiment demonstrated that let-7b-5p overexpression increased hepatocyte fatty acid transport and inhibited adipocyte-like cell thermogenesis, whereas let-7b-5p inhibitor exerted the opposite effects. Conclusion: Hepatocyte TGF-β-let-7b-5p signaling promotes HFD-induced steatosis and obesity by reducing mitochondrial oxidative phosphorylation and suppressing white-to-beige fat conversion. This effect of hepatocyte TGF-β signaling in metabolism is partially associated with exosomal let-7b-5p.

SUBMITTER: Zhao J

PROVIDER: S-EPMC9134819 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

Zhao Jinfang J Hu Lilin L Gui Wenfang W Xiao Li L Wang Weijun W Xia Jing J Fan Huiqian H Li Zhonglin Z Zhu Qingjing Q Hou Xiaohua X Chu Huikuan H Seki Ekihiro E Yang Ling L

Hepatology communications 20220111 6

Transforming growth factor beta (TGF-β) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-β signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high-fat diet (HFD) in hepatocyte-specific TGF-β receptor II-deficient (Tgfbr2<sup>ΔHEP</sup> ) and Tgfbr2<sup>flox/flox</sup> mice. In addition, browning of white adipose ...[more]

PMID: 35018737

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Project description:ObjectiveHigh intake of caffeoylquinic acid (CQA)-rich dietary supplements, such as green coffee bean extracts, offers health-promoting effects on maintaining metabolic homeostasis. Similar to many active herbal ingredients with high pharmacological activities but low bioavailability, CQA has been reported as a promising thermogenic agent with anti-obesity properties, which contrasts with its poor oral absorption. Intestinal tract is the first site of CQA exposure and gut microbes might react quickly to CQA. Thus, it is of interest to explore the role of gut microbiome and microbial metabolites in the beneficial effects of CQA on obesity-related disorders.ResultsOral CQA supplementation effectively enhanced energy expenditure by activating browning of adipose and thus ameliorated obesity-related metabolic dysfunctions in high fat diet-induced obese (DIO) mice. Here, 16S rRNA gene amplicon sequencing revealed that CQA treatment remodeled the gut microbiota to promote its anti-obesity actions, as confirmed by antibiotic treatment and fecal microbiota transplantation. CQA enriched the gut commensal species Limosilactobacillus reuteri (L. reuteri) and stimulated the production of short-chain fatty acids, especially propionate. Mono-colonization of L. reuteri or low-dose CQA treatment did not reduce adiposity in DIO mice, while their combination elicited an enhanced thermogenic response, indicating the synergistic effects of CQA and L. reuteri on obesity. Exogenous propionate supplementation mimicked the anti-obesity effects of CQA alone or when combined with L. reuteri, which was ablated by the monocarboxylate transporter (MCT) inhibitor 7ACC1 or MCT1 disruption in inguinal white adipose tissues to block propionate transport.ConclusionsOur data demonstrate a functional axis among L. reuteri, propionate, and beige fat tissue in the anti-obesity action of CQA through the regulation of thermogenesis. These findings provide mechanistic insights into the therapeutic use of herbal ingredients with poor bioavailability via their interaction with the gut microbiota. Video Abstract.

Dataset Information

Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

Publications

Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

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