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

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.

Neuronal modulation of hepatic lipid accumulation induced by bingelike drinking

“…AgRP inhibits sympathetic activity in the white adipose tissue to limit lipolysis (38). We have also shown that intracerebroventricular infusion of AgRP suppresses sympathetic activity in the liver (29). Moreover, AgRP neurons mediate the stimulatory effects of leptin on sympathetic activity in the adipose tissue and liver (2).…”

“…The brain regulates peripheral lipid metabolism by modulating the function of the autonomic nervous system innervating peripheral metabolic tissues. In particular, the AgRP neuropeptide inhibits sympathetic nervous system (SNS) activity in both the white adipose tissue and liver (29,38). To this end, we sought to determine if intact SNS function is required for the development of hepatic steatosis induced by bingelike alcohol consumption.…”

“…AgRP neurons regulate peripheral tissues including liver and adipose tissues via modulation of the autonomic nervous system innervating these tissues (2). For example, we recently showed that AgRP inhibits hepatic sympathetic activity and that eliminating AgRP in leptin-deficient mice alters both hepatic lipid accumulation and distribution in an age-dependent manner (29).…”

Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci

“…The proposed mechanism for this occurrence is that loss of SORCS3 expressed in agouti-related peptide (AGRP) neurons leads to unchecked production of circulating AGRP ( Henry et al, 2015 ). ARGP is well described to cause enhanced food intake, decreased locomotor activity, decreased use of lipids as metabolic fuel, and overall increased adiposity ( Maier et al, 2018 ; Beutler et al, 2020 ). One limitation of GTEx data is a very small sample size of hypothalamus data, our data show that reduced expression of SORCS3 in the pituitary gland is related to high levels of TC and an increased overall risk for PAD, potentially through increased circulating AGRP diverting energy metabolism away from lipid sources.…”

Therapeutic effects of Co-Venenum Bufonis Oral Liquid on radiation-induced esophagitis in rats

“…Although a direct delivery of radiation to the tumor of the patient has been applied, radiotherapy induced acute and long-term damages to the surrounding normal tissues are still a common complication [1,5,21]. Radiation-induced esophagitis is one of the most common inflammatory reactions to radiotherapy in thoracic tumor [20,24,29].…”