FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice

Zhao, Cuiqing; Liu, Yanlong; Xiao, Jian; Li, Liming; Chen, Shaoyu; Mohammadi, Moosa; McClain, Craig J.; Li, Xiaokun; Feng, Wenke

doi:10.1194/jlr.m058610

Cited by 90 publications

(96 citation statements)

References 57 publications

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“…Thus, FGF21 is part of a liver-brain feedback loop that limits the consumption of simple sugars. Notably, FGF21 is also strongly induced in liver by alcohol and contributes to alcohol-induced adipose tissue lipolysis in a mouse model of chronic binge alcohol consumption (12). Our data suggest the existence of an analogous feedback loop, wherein liver-derived FGF21 acts on brain to limit the consumption of alcohol.…”

Section: Discussionmentioning

confidence: 65%

“…FGF19 is induced by bile acids in the small intestine to regulate bile acid homeostasis and metabolism in the liver (9). FGF21 is induced in liver and released into the blood in response to various metabolic stresses, including high-carbohydrate diets and alcohol (10)(11)(12). Notably, FGF21 was recently associated in a human GWAS study with macronutrient preference, including changes in carbohydrate, protein, and fat intake (13).…”

Section: −12mentioning

confidence: 99%

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KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Schumann

Liu

O’Reilly

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

222

223

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Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10 −12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

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Section: Discussionmentioning

confidence: 65%

Section: −12mentioning

confidence: 99%

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Schumann

Liu

O’Reilly

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

222

223

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“…5) and modest reduction (∼20%) in Cyp3a11 mRNA expression in liver (Woolsey et al, 2015). Since hepatic expression and plasma FGF21 levels are also elevated in a mouse model of ALD (Zhao et al, 2015), it would appear that FGF21 impacts CYP3A expression in ALD differently than in NAFLD.…”

Section: Discussionmentioning

confidence: 99%

A Fibroblast Growth Factor 21–Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease

et al. 2016

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Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipidand glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat dietinduced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4. Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD.

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“…Alcohol has known deleterious effects on the pancreas which may explain this decrease in insulin secretion. Also alcohol induces systemic elevation of cathecholamines leading to activation of lipolytic enzymes [20] and decreasing insulin secretion. Insulin secretion shares an important relationship with insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Effect of Binge Drinking on Glucose Metabolism in Occasional Drinkers: An Experimental Study

Ngandeu¹,

Mbanya²,

Lontchi-Yimagou³

et al. 2018

OJEMD

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Binge drinking is a major public health problem that affects all age groups. Its relation to the risk of impaired glucose metabolism and diabetes is unclear due to controversial findings in animal models and lack of studies in humans. We performed an experimental study on 10 adult volunteers (7M/3F) under the age of 40 who were occasional binge drinkers. In all participants, we performed a baseline two-hour euglycemic hyperinsulinemic clamp at 80 mU·m -²·min -1 at baseline for comparison with an age and sex matched control population of non-drinkers. On a second occasion, before and after ingestion of 78 g of alcohol (beer) in 2 hrs we also measured insulin sensitivity using a 15-minute short insulin tolerance test in drinkers. Blood glucose was also measured every 15 mins over 2 hours during alcohol ingestion. Volunteers were aged 27.6 ± 5.7 years, with a BMI of 23.1 ± 2.8 kg/m², and ALAT of 24.7 ± 3.0 UI/L. Insulin sensitivity evaluated by the clamp technique was higher in occasional drinkers (M = 12.7 ± 3.4 mg·kg ·min -1 in non-drinkers, p = 0.011). Acute alcohol ingestion was associated with a non-significant trends towards improved glucose disappearance during short insulin tolerance test (KITT 2.53% ± 0.22%/min before vs. 3.11% ± 1.15%/min after; p = 0.122).Beer consumption induced a significant increase in capillary glycaemia of 78%How to cite this paper: Ngandeu, N

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FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice

Cited by 90 publications

References 57 publications

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

A Fibroblast Growth Factor 21–Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease

Effect of Binge Drinking on Glucose Metabolism in Occasional Drinkers: An Experimental Study

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