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J Lipid Res. 2020 Mar;61(3):387-402. doi: 10.1194/jlr.RA119000542. Epub 2020 Jan 21.

The citrus flavonoid nobiletin confers protection from metabolic dysregulation in high-fat-fed mice independent of AMPK.

Author information

1
Molecular Medicine, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada N6A 5B7.
2
Departments of Biochemistry University of Western Ontario, London, Ontario, Canada N6A 5B7.
3
Medicine, University of Western Ontario, London, Ontario, Canada N6A 5B7.
4
Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
5
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
6
Molecular Medicine, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada N6A 5B7 mhuff@uwo.ca.

Abstract

Obesity, dyslipidemia, and insulin resistance, the increasingly common metabolic syndrome, are risk factors for CVD and type 2 diabetes that warrant novel therapeutic interventions. The flavonoid nobiletin displays potent lipid-lowering and insulin-sensitizing properties in mice with metabolic dysfunction. However, the mechanisms by which nobiletin mediates metabolic protection are not clearly established. The central role of AMP-activated protein kinase (AMPK) as an energy sensor suggests that AMPK is a target of nobiletin. We tested the hypothesis that metabolic protection by nobiletin required phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in mouse hepatocytes, in mice deficient in hepatic AMPK (Ampkβ1 -/-), in mice incapable of inhibitory phosphorylation of ACC (AccDKI), and in mice with adipocyte-specific AMPK deficiency (iβ1β2AKO). We fed mice a high-fat/high-cholesterol diet with or without nobiletin. Nobiletin increased phosphorylation of AMPK and ACC in primary mouse hepatocytes, which was associated with increased FA oxidation and attenuated FA synthesis. Despite loss of ACC phosphorylation in Ampkβ1 -/- hepatocytes, nobiletin suppressed FA synthesis and enhanced FA oxidation. Acute injection of nobiletin into mice did not increase phosphorylation of either AMPK or ACC in liver. In mice fed a high-fat diet, nobiletin robustly prevented obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and it improved energy expenditure in Ampkβ1 -/-, AccDKI, and iβ1β2AKO mice to the same extent as in WT controls. Thus, the beneficial metabolic effects of nobiletin in vivo are conferred independently of hepatic or adipocyte AMPK activation. These studies further underscore the therapeutic potential of nobiletin and begin to clarify possible mechanisms.

KEYWORDS:

adenosine monophosphate-activated protein kinase; fatty acid oxidation; hypolipidemic drugs; insulin resistance; lipogenesis; obesity; steatohepatitis

PMID:
31964763
PMCID:
PMC7053837
[Available on 2021-03-01]
DOI:
10.1194/jlr.RA119000542

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