Leptin is an adipocyte-derived hormone that circulates at levels proportional to the body's fat mass, which conveys the abundance of peripheral energy stores to the brain. We have previously shown that leptin acts centrally to suppress hepatic lipid content via activation of the sympathetic nervous system;we have further shown that central leptin resistance in the PI3K signaling pathway leads to decreased hepatic sympathetic tone and increased triglyceride levels without hyperphagia and weight gain. These results indicate that central cellular leptin resistance manifests as hepatic steatosis independent of obesity. Interestingly, like obesity, starvation also induces severe hepatic steatosis. This is generally thought to be caused by the increased delivery of free fatty acids to the liver due to th mobilization of the white adipose tissue. In this proposal, we will test the hypothesis that the decline of leptin levels during starvation is required for the development of hepatic steatosis. We will evaluate whether the increase of hepatic lipid stores in starvation serves to ensure sustained energy production from the liver to meet the energy demands of extra-hepatic tissues. We further propose that Agouti-related protein (AGRP) is a downstream effector of leptin's action on hepatic lipid metabolism in starvation, and we will define the neuronal circuitry underlying AGRP's effects. Finally, we will explore whether antagonism of AGRP in wildtype animals would alleviate hepatic steatosis in diet-induced obesity. This study, if successful, will establish that starvation-induced liver steatosis is not just a passive process caused by increased free fatty acid flux to the liver, as commonly thought, but rather an integral component of the overall adaptive regulation by leptin to ensure energy availability during long period of food deprivation. This mechanism may also operate in diet-induced obesity in that impairment of leptin signaling due to leptin resistance is perceived by the brain as a state of negative energy balance, triggering similar adaptive responses as in starvation and contributing to non-alcoholic fatty liver diseases.

Public Health Relevance

In this proposal, we will elucidate a novel mechanism underlying starvation-induced hepatic steatosis. We propose that starvation-induced liver steatosis is not just a passive process caused by increased fatty acid flux to the liver, as commonly thought, but rather an integral component of the overall adaptive regulation by leptin to ensure energy availability during long period of food deprivation. This mechanism may also operate in diet- induced obesity in that impairment of leptin signaling due to leptin resistance is perceived by the brain as a state of starvation, triggering similar adaptive responses and thereby contributing to non-alcoholic fatty liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK080427-06A1
Application #
8578968
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2008-02-01
Project End
2017-05-31
Budget Start
2013-07-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$341,475
Indirect Cost
$123,975
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Warne, James P; Xu, Allison W (2013) Metabolic transceivers: in tune with the central melanocortin system. Trends Endocrinol Metab 24:68-75
Warne, James P; Varonin, Jillian M; Nielsen, Sofie S et al. (2013) Coordinated regulation of hepatic energy stores by leptin and hypothalamic agouti-related protein. J Neurosci 33:11972-85
Newton, A Jamila; Hess, Simon; Paeger, Lars et al. (2013) AgRP innervation onto POMC neurons increases with age and is accelerated with chronic high-fat feeding in male mice. Endocrinology 154:172-83
Olofsson, Louise E; Unger, Elizabeth K; Cheung, Clement C et al. (2013) Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance. Proc Natl Acad Sci U S A 110:E697-706
Warne, James P; Alemi, Farzad; Reed, Alison S et al. (2011) Impairment of central leptin-mediated PI3K signaling manifested as hepatic steatosis independent of hyperphagia and obesity. Cell Metab 14:791-803