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. 2009 May;150(5):2169-74.
doi: 10.1210/en.2008-1271. Epub 2009 Jan 15.

Leptin augments the acute suppressive effects of insulin on hepatic very low-density lipoprotein production in rats

Wan Huang  1 , Anantha Metlakunta, Nikolas Dedousis, Heidi K Ortmeyer, Maja Stefanovic-Racic, Robert M O'Doherty
Affiliations

Leptin augments the acute suppressive effects of insulin on hepatic very low-density lipoprotein production in rats

Wan Huang et al. Endocrinology. 2009 May.

Abstract

It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg x min(-1)) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 microg/kg x min(-1)) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (approximately 50%, P < 0.01), increased liver TGs (approximately 20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (approximately 50%, P < 0.01) and increased fatty acid oxidation (approximately 50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.

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Figures

Figure 1
Figure 1
The effects of insulin and leptin on plasma VLDL-TGs. Fasted (18 h) rats fed a standard chow diet received a continuous iv infusion of either vehicle, leptin, insulin, or combined leptin and insulin as described in Materials and Methods. Subsequently blood was taken and TGs were measured as described in Materials and Methods (n = minimum of six animals/group). Results are presented as mean ± se. Significant differences are indicated.
Figure 2
Figure 2
The effects of insulin and leptin on liver VLDL secretion and skeletal muscle lipoprotein lipase activity. A, Fasted (18 h) rats fed a standard chow diet received an injection of the LPL inhibitor toloxapol and a continuous iv infusion of vehicle, insulin, or leptin as described in Materials and Methods. Blood samples were obtained before the beginning of infusions and after the completion of infusions. Subsequently plasma VLDL-TG was measured as described in Materials and Methods. B, Fasted (18 h) rats fed a standard chow diet received a continuous iv infusion of vehicle, insulin, or leptin as described in Materials and Methods. Subsequently skeletal muscle was isolated and LPL activity was measured as described in Materials and Methods (n = minimum of six animals/group). Results are presented as mean ± se. Significant differences are indicated.
Figure 3
Figure 3
The effects of insulin and leptin on plasma apoB-100 and apoB-48. Fasted (18 h) rats fed a standard chow diet received a continuous iv infusion of vehicle, insulin, leptin, or combined leptin and insulin as described in Materials and Methods. Subsequently blood was taken, VLDL was isolated, and apoB-100 and apoB-48 were measured by immunoblot as described in Materials and Methods. Autoradiograph composites from each experimental condition for apoB-100 and apoB-48 and albumin are presented and the quantification of the total data for each condition is presented below each autoradiograph (n = minimum of six animals/group). Results are presented as mean ± se. Significant differences are indicated. A, Vehicle vs. insulin; B, insulin vs. leptin/insulin; C, vehicle vs. leptin. PL, Plasma.
Figure 4
Figure 4
The effects of insulin and leptin on liver apoB-100 and apoB-48. Fasted (18 h) rats fed a standard chow diet received a continuous iv infusion of vehicle, insulin, leptin, or combined leptin and insulin as described in Materials and Methods. Subsequently liver was taken and apoB-100 and apoB-48 were measured by immunoblot as described in Materials and Methods. Autoradiograph composites from each experimental condition for apoB-100 and apoB-48 and tubulin are presented and the quantification of the total data for each condition is presented below each autoradiograph (n = minimum of six animals/group). Results are presented as mean ± se. Significant differences are indicated. A, Vehicle vs. insulin; B, insulin vs. leptin/insulin; C, vehicle vs. leptin. LIV, Liver.
Figure 5
Figure 5
The effects of insulin and leptin on liver TG levels. Fasted (18 h) rats fed a standard chow diet received a continuous iv infusion of vehicle, insulin, leptin, or combined leptin and insulin as described in Materials and Methods. Subsequently liver was taken and TGs were measured as described in Materials and Methods (n = minimum of six animals/group). Results are presented as mean ± se. Significant differences are indicated.
Figure 6
Figure 6
The effects of insulin and leptin on liver ACC phosphorylation and fatty acid oxidation. Fasted (18 h) rats fed a standard chow diet received a continuous iv infusion of vehicle, insulin, leptin, or combined leptin and insulin as described in Materials and Methods. Subsequently liver was taken and ACC phosphorylation was measured by immunoblot (A) or fatty acid oxidation was assessed (B) as described in Materials and Methods. For phospho (p) and total (t) ACC, autoradiograph composites from each experimental condition are presented and the quantification of the total data for each condition is presented below each autoradiograph. B, n = minimum of six animals/group. Results are presented as mean ± se. Significant differences are indicated. Lep, Leptin; Ins, insulin.
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