Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels

Abstract

Leptin reduces body weight in ob/ob mice by decreasing food intake and increasing energy expenditure; however, the mechanisms by which it does the latter are not known. Here we report that 30% of the weight loss induced by leptin treatment of ob/ob mice is due to changes in energy expenditure. In assessing leptin's effects on specific tissues, we found that hepatic basal metabolic rate was paradoxically decreased 1.7-fold with leptin treatment, which was the result of a 1.6-fold reduction in mitochondrial volume density and altered substrate oxidation kinetics. The altered kinetics were associated with a decrease in protein levels of 2 mitochondrial respiratory chain components-cytochrome c oxidase subunit VIa and cytochrome c oxidase subunit IV. In addition to reduced hepatic metabolism, there was reduced long chain fatty acid production and a 2.5-fold increase in hepatic lipid export, both of which explain the reduced steatosis in leptin-treated animals. These data help clarify the role of the liver in leptin-mediated weight loss and define the mechanisms by which leptin alters hepatic metabolism and corrects steatosis.O besity is a significant global health problem and a leading contributor to morbidity and mortality in the developed and developing world. Obese individuals are at a higher risk for the development of coronary heart disease, diabetes, hypertension, and cancer (1). A fuller understanding of the biological underpinnings of this disorder remains critical for the development of new treatments.Body weight is maintained at a stable level by a tightly controlled balance between energy intake and expenditure. While food intake is well appreciated as contributing to the regulation weight, it is increasingly clear that differences in energy expenditure, basal metabolic rates, and/or adaptive thermogenesis, are also important variables that contribute to obesity (2-4). For example, low energy expenditure is highly predictive of future weight gain (5, 6). Furthermore, weight loss in humans is met with a compensatory decrease in metabolic rate and increase in appetite, which work in concert to resist further changes in weight (7). Pharmacological agents that augment the increase in resting metabolic rate induced by exercise, and thus counteract the compensatory metabolic changes discussed above, could potentially be valuable tools in our battle against morbid obesity (1,8,9).Leptin is an adipocyte-secreted, negative feedback hormone that acts on the hypothalamus to regulate both food intake and energy expenditure (10, 11). Leptin-deficient ob/ob mice show markedly reduced levels of energy expenditure and become obese even when pair fed compared with littermate controls (12, 13). This and other studies have indicated that leptin's effects on caloric intake in treated ob/ob mice only partially account for leptin-mediated weight loss (12,(14)(15)(16). Thus in addition to reducing caloric intake, leptin treatment of ob/ob mice increases total energy expenditure, selectively promotes fat metabolism, and prevents...

Physiological adaptations to reproduction II. Mitochondrial adjustments in livers of lactating mice

“…For example, during lactation, there is a profound reduction in circulating leptin levels (Kunz et al, 1999;Woodside et al, 2000), which potentially stimulates food intake (Speakman and Król, 2011). In accordance with our results, it has been shown that an increase in leptin levels is associated with reduced mitochondrial volume density and altered substrate oxidation kinetics in liver of mice (Singh et al, 2009). Therefore, it is possible that during lactation the leptin levels cannot be reduced under a specific rate, regardless of the number of pups that can be assigned to a female, explaining why we did not find differences within the reproductive females.…”

Structural profiling of endogenous S-nitrosocysteine residues reveals unique features that accommodate diverse mechanisms for protein S-nitrosylation

“…The regulation of liver metabolism is attributed to the leptin-dependent repression of liver stearoyl-CoA desaturase-1, the rate limiting step in monosaturated fat biosynthesis (28). In addition, recent data indicate that leptin also regulates liver mitochondrial respiratory chain protein expression, mitochondrial function and structure (29), remarkably similar to the previously recognized regulation of mitochondrial function by NO (30,31). Interestingly, delivery of S-nitroso-N-acetylcysteine by gavage to ob/ob mice prevented the development of fatty liver (32).…”

A Role for Hepatic Leptin Signaling in Lipid Metabolism via Altered Very Low Density Lipoprotein Composition and Liver Lipase Activity in Mice

“…For example, restricting food intake in ob/ob mice cannot improve lipid metabolism as effectively as leptin treatment. 6,7 In addition, lipodystrophic mice and humans, which have little to no adipose tissue and are hypoleptinemic, also display hyperlipidemia and hepatic steatosis, and these symptoms are ameliorated by leptin. 8,9 Clearly, leptin has effects on lipid metabolism independent of its effects on body weight.…”

“…Indeed, leptin receptors are found in the liver, 10,11 and leptin administration to ob/ob mice elicits many changes in the expression of genes involved with lipid metabolism in the liver. 6,8,12 Furthermore, leptin treatment in ob/ob mice can reverse hepatic steatosis, 7 potentially due to direct effects of leptin on the liver. 13,14 To address the direct effects of leptin on the liver, Cohen et al 15 knocked out leptin receptors specifically in hepatocytes.…”