Abstract
Diet-related obesity is a major metabolic disorder. Excessive fat mass is associated with type 2 diabetes, hepatic steatosis, and arteriosclerosis. Dysregulation of lipid metabolism and adipose tissue function contributes to diet-induced obesity. Here, we report that β-arrestin-1 knock-out mice are susceptible to diet-induced obesity. Knock-out of the gene encoding β-arrestin-1 caused increased fat mass accumulation and decreased whole-body insulin sensitivity in mice fed a high-fat diet. In β-arrestin-1 knock-out mice, we observed disrupted food intake and energy expenditure and increased macrophage infiltration in white adipose tissue. At the molecular level, β-arrestin-1 deficiency affected the expression of many lipid metabolic genes and inflammatory genes in adipose tissue. Consistently, transgenic overexpression of β-arrestin-1 repressed diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Thus, our findings reveal that β-arrestin-1 plays a role in metabolism regulation.
Highlights
-Arrestins (-arrestin-1 and -arrestin-2) are traditionally regarded as terminators of G protein-coupled receptor signaling and regulators of receptor desensitization following stimulation [5, 6]
Our recent study demonstrated that -arrestin-2, which is located primarily in the cytoplasm, functions as an indispensable scaffold that links Akt and Src to the insulin receptor following insulin stimulation, and a deficiency of -arrestin-2 contributes to insulin resistance [11]
Previous studies have shown that -arrestin-1 mediates insulin receptor substrate-1 and glucagon-like peptide-1 signaling in -cells
Summary
Animals—-Arrestin-1 knock-out (arr1-ko) and arr2-ko mice were provided by Dr Robert J. Paraffin embedding, sectioning, and hematoxylin and eosin staining were performed according to standard protocols. A, body weight of arr1-tg (Tg) and arr1-ko (KO) mice and their wild-type littermates (WT) fed either a RD or HFD (n ϭ 10/group). B, body weight gain of arr1-tg and arr1-ko mice and their wild-type littermates fed either a RD or HFD for 14 weeks (n ϭ 10/group). C, body length of arr1-tg and arr1-ko mice and their wild-type littermates fed either a RD or HFD (n ϭ 10/group). D, blood TGs and free fatty acids of arr1-tg and arr1-ko mice and their wild-type littermates fed a RD or HFD (n ϭ 10/group). E, blood leptin levels of arr1-tg and arr1-ko mice and their wild-type littermates fed a RD or HFD (n ϭ 10/group). Statistical Analysis—In vitro and in vivo data were analyzed by Student’s t test and analysis of variance followed by Student’s t test, respectively
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