Liver Triglyceride Secretion and Lipid Oxidative Metabolism Are Rapidly Altered by Leptin in Vivo

Huang, Wan; Dedousis, Nikolaos; Bandi, Archana; Lopaschuk, Gary D.; O’Doherty, Robert M.

doi:10.1210/en.2005-0731

Cited by 103 publications

(104 citation statements)

References 42 publications

(71 reference statements)

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“…Consistent with the literature, 14,32 our data do support the fact that direct leptin action on the liver plays an antisteatotic role, but the level of hepatic steatosis in Lepr flox/flox AlbCreþ mice was not as severe as in livers of db/db mice. Furthermore, unlike db/db mice with a global loss of leptin signaling, lean mice with a liver-specific loss of leptin signaling have normal total fasting plasma triglycerides and cholesterol levels.…”

Section: Leprsupporting

confidence: 93%

A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice

et al. 2012

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Obesity is highly associated with dyslipidemia and cardiovascular disease. However, the mechanism behind this association is not completely understood. The hormone leptin may be a molecular link between obesity and dysregulation of lipid metabolism. Leptin can affect lipid metabolism independent of its well-known effects on food intake and energy expenditure, but exactly how this occurs is ill-defined. We hypothesized that since leptin receptors are found on the liver and the liver plays an integral role in regulating lipid metabolism, leptin may affect lipid metabolism by acting directly on the liver. To test this hypothesis, we generated mice with a hepatocyte-specific loss of leptin signaling. We previously showed that these mice have increased insulin sensitivity and elevated levels of liver triglycerides compared with controls. Here, we show that mice lacking hepatic leptin signaling have decreased levels of plasma apolipoprotein B yet increased levels of very low density lipoprotein (VLDL) triglycerides, suggesting alterations in triglyceride incorporation into VLDL or abnormal lipoprotein remodeling in the plasma. Indeed, lipoprotein profiles revealed larger apolipoprotein B-containing lipoprotein particles in mice with ablated liver leptin signaling. Loss of leptin signaling in the liver was also associated with a substantial increase in lipoprotein lipase activity in the liver, which may have contributed to increased lipid droplets in the liver. Conclusion: Lack of hepatic leptin signaling results in increased lipid accumulation in the liver and larger, more triglyceride-rich VLDL particles. Collectively, these data reveal an interesting role for hepatic leptin signaling in modulating triglyceride metabolism. (HEPATOLOGY 2013;57:543-554) D espite the well-accepted link between obesity, diabetes, and dyslipidemia, the molecular mechanisms that drive this association are not understood. The hormone leptin is a potential link between obesity and abnormal lipid metabolism. Leptin is secreted from adipose tissue and acts on the hypothalamus to reduce food intake and increase energy expenditure.1,2 Thus, leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are hyperphagic and obese. However, these mice also display hypertriglyceridemia, 3 hypercholesterolemia, 3 hepatic steatosis, 4 and impaired lipid tolerance. 5 Several studies suggest that these effects on lipid metabolism are independent of leptin's effects on food intake and obesity. 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.The manner by which leptin directly affects lipid metabolism is not well understood. We hypothesized Abbreviations: Ad-b-gal, adenovirus exp...

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Section: Leprsupporting

confidence: 93%

A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice

et al. 2012

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“…PAS-leptin shifted fuel selection towards lipid oxidation. This could have been mediated either by direct stimulation of lipid metabolism or by an inhibitory effect on energy intake [28][29][30]. Indeed, the latter phenomenon was confirmed in both cohorts used in this study.…”

Section: Discussionsupporting

confidence: 70%

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

et al. 2016

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Aims/hypothesis Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology. Methods A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition.Results In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements. Conclusions/interpretation The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.

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“…Similarly, leptin has been shown to increase hepatic fatty acid oxidation and plasma triglyceride as well as reduce triglyceride secretion into plasma [55,56]. However, this study found minimal correlations between leptin and lipid profiles.…”

contrasting

confidence: 66%

Liver function parameters, cholesterol, and phospholipid α-linoleic acid are associated with adipokine levels in overweight and obese adults

Gray¹,

Steyn²,

Davies³

et al. 2014

Nutrition Research

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Liver Triglyceride Secretion and Lipid Oxidative Metabolism Are Rapidly Altered by Leptin in Vivo

Cited by 103 publications

References 42 publications

A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice

A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

Liver function parameters, cholesterol, and phospholipid α-linoleic acid are associated with adipokine levels in overweight and obese adults

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