Abstract
Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis.
Highlights
Leptin is a central mediator of endocrine circuits that regulate energy homeostasis providing feedback information to the hypothalamus regarding the energy status and decreasing body weight [1]
C, control rats; CI, rats receiving acute central administration of insulin; PF, pair-fed rats; PFI, pair-fed rats treated with insulin; L, rats treated with chronic icv leptin infusion and LI, rats treated with leptin plus insulin. iBAT, interscapular brown adipose tissue. * p < 0.05, ** p < 0.01 vs. C; # p < 0.05, ## p < 0.01 vs. PF
Rats treated with leptin administration of insulin (CI); pair-fed rats (PF); pair-fed rats treated with insulin (PFI); rats plus insulin (LI). (B) Relative phosphorylated (p) signal transducer and activator of transcription (STAT)5 on tyrosine treated with chronic icv leptin infusion (L) and rats treated with leptin plus insulin (LI). (B) Rela694 protein levels (C) Relative phosphorylated extracellular signal-regulated kinases (ERK) on threonine tive phosphorylated (p) signal transducer and activator of transcription (STAT)5 on tyrosine 694
Summary
Leptin is a central mediator of endocrine circuits that regulate energy homeostasis providing feedback information to the hypothalamus regarding the energy status and decreasing body weight [1]. Insulin is a critical regulator of energy balance, acting in the same hypothalamic areas as leptin to suppress feeding [2]. Leptin regulates energy homeostasis by acting in peripheral tissues, with central administration modulating peripheral metabolism through changes in insulin sensitivity [3]. The liver is a key organ in lipid metabolism, with leptin reducing hepatic lipid content by decreasing the activity of lipogenic enzymes and up-regulating the expression of those implicated in lipolysis [4]. Insulin increases levels of hepatic malic enzyme [6] as well as the activity of glucose-6-phosphate dehydrogenase (G6PD) in the liver [7]. An increase in the levels and activity of these “lipogenic” enzymes is crucial to supply the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) for lipogenesis [8]
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