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UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver.

ABSTRACT: Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency. Defects in UCP1 and brown adipose tissue thermogenesis subject animals to chronic cold stress and elicit compensatory responses to generate heat. How UCP1 regulates white adipose tissue (WAT) lipid biology and tissue crosstalk is not completely understood. Here, we probed the effect of UCP1 deficiency on FA metabolism in inguinal and epididymal WAT and investigated how these metabolic perturbations influence hepatic lipid homeostasis. We report that at standard housing temperature (21°C), loss of UCP1 induces inguinal WAT de novo lipogenesis through transcriptional activation of the lipogenic gene program and elevated GLUT4. Inguinal adipocyte hyperplasia and depot expansion accompany the increase in lipid synthesis. We also found that UCP1 deficiency elevates adipose stearoyl-CoA desaturase gene expression, and increased inguinal WAT lipolysis supports the transport of adipose-derived palmitoleate (16:1n7) to the liver and hepatic triglyceride accumulation. The observed WAT and liver phenotypes were resolved by housing animals at thermoneutral housing (30°C). These data illustrate depot-specific responses to impaired BAT thermogenesis and communication between WAT and liver in UCP1-/- mice.

SUBMITTER: Bond LM

PROVIDER: S-EPMC5794418 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver.

Bond Laura M LM Ntambi James M JM

Journal of lipid research 20171203 2

Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency. Defects in UCP1 and brown adipose tissue thermogenesis subject animals to chronic cold stress and elicit compensatory responses to generate heat. How UCP1 regulates white adipose tissue (WAT) lipid biology and tissue crosstalk is not completely understood. Here, we probed the effect of UCP1 deficiency on FA metabolism in inguin ...[more]

PMID: 29203476

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Project description:Background & aims: The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model.MethodsAdipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed.ResultsPatients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids.ConclusionsPro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD.Impact and implicationsWe report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.

Dataset Information

UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver.

Publications

UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver.

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