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Endocrinology. 2018 Jun 1;159(6):2408-2420. doi: 10.1210/en.2018-00040.

Regulation of Hepatic Lipid Accumulation and Distribution by Agouti-Related Protein in Male Mice.

Author information

1
Diabetes Center, University of California, San Francisco, San Francisco, California.
2
Department of Chemistry, University of California, Berkeley, Berkeley, California.
3
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California.
4
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California.
5
Department of Medicine, University of California, San Francisco, San Francisco, California.
6
Department of Anatomy, University of California, San Francisco, San Francisco, California.

Abstract

Proper regulation of energy metabolism requires neurons in the central nervous system to respond dynamically to signals that reflect the body's energy reserve, and one such signal is leptin. Agouti-related protein (AgRP) is a hypothalamic neuropeptide that is markedly upregulated in leptin deficiency, a condition that is associated with severe obesity, diabetes, and hepatic steatosis. Because deleting AgRP in mice does not alter energy balance, we sought to determine whether AgRP plays an indispensable role in regulating energy and hepatic lipid metabolism in the sensitized background of leptin deficiency. We generated male mice that are deficient for both leptin and AgRP [double-knockout (DKO)]. DKO mice and ob/ob littermates had similar body weights, food intake, energy expenditure, and plasma insulin levels, although DKO mice surprisingly developed heightened hyperglycemia with advancing age. Overall hepatic lipid content was reduced in young prediabetic DKO mice, but not in the older diabetic counterparts. Intriguingly, however, both young and older DKO mice had an altered zonal distribution of hepatic lipids with reduced periportal lipid deposition. Moreover, leptin stimulated, whereas AgRP inhibited, hepatic sympathetic activity. Ablating sympathetic nerves to the liver, which primarily innervate the portal regions, produced periportal lipid accumulation in wild-type mice. Collectively, our results highlight AgRP as a regulator of hepatic sympathetic activity and metabolic zonation.

PMID:
29750244
DOI:
10.1210/en.2018-00040
[Indexed for MEDLINE]

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