Long-Term Effects of Central Leptin and Resistin on Body Weight, Insulin Resistance, and β-Cell Function and Mass by the Modulation of Hypothalamic Leptin and Insulin Signaling

Abstract

To determine the long-term effect of central leptin and resistin on energy homeostasis, peripheral insulin resistance, and beta-cell function and mass, intracerebroventricular (ICV) infusion of leptin (3 ng/h), resistin (80 ng/h), leptin plus resistin, and cerebrospinal fluid (control) was conducted by means of an osmotic pump for 4 wk on normal rats and 90% pancreatectomized diabetic rats fed 40% fat-energy diets. Overall, the effects were greater in diabetic rats than normal rats. Leptin infusion, causing a significant reduction in food intake, decreased body weight and epididymal fat. However, resistin and leptin plus resistin reduced epididymal fat with decreased serum leptin levels in comparison with the control. Unlike serum leptin, only resistin infusion lowered serum resistin levels. Central leptin increased glucose infusion rates during euglycemic hyperinsulinemic clamp and suppressed hepatic glucose production in the hyperinsulinemic state in comparison with the control. However, central leptin did not affect glucose-stimulated insulin secretion and beta-cell mass. Central resistin infusion also increased peripheral insulin sensitivity, but not as much as leptin. Unlike leptin, resistin significantly increased first-phase insulin secretion during hyperglycemic clamp and beta-cell mass by augmenting beta-cell proliferation. These metabolic changes were associated with hypothalamic leptin and insulin signaling. ICV infusion of leptin potentiated signal transducer and activator of transcription 3 phosphorylation and attenuated AMP kinase in the hypothalamus, but resistin had less potent effects than leptin. Leptin enhanced insulin signaling by potentiating IRS2-->Akt pathways, whereas resistin activated Akt without augmenting insulin receptor substrate 2 phosphorylation. In conclusion, long-term ICV infusion of leptin and resistin independently improved energy and glucose homeostasis by modulating in different ways hypothalamic leptin and insulin signaling.

Expression and effect of resistin on bovine and rat granulosa cell steroidogenesis and proliferation

“…Resistin has been reported to stimulate proliferation of different cellular types (Calabro et al 2004, Ort et al 2005, Mu et al 2006, Park et al 2008. Conversely, resistin-13 peptide, a fragment of human resistin possessing some biological activity of the entire hormone, inhibited the proliferation of the breast cancer …”

Hypothalamic control of energy and glucose metabolism

“…Chronic studies, on the other hand, show increased muscle glucose uptake in chow fed rats [150,152]. Conversely, although leptin is able to influence hepatic glucose flux in DIO rats [154], chronic ICV leptin in DIO rats is unable to restore insulin-induced increases in glucose uptake [153]. However, these seemingly discordant results may be secondary to different diets, leptin doses, and/or the sex of the rats.…”

“…Given that leptin serves as long-term adiposity signal, it follows that chronic ICV administration of leptin would have more potent effects on glucose homeostasis. Considering that high fat diets and obesity have been shown to cause CNS leptin resistance in regards to anorexia, it is surprising that in several different models, including DIO rats, short term overfed rats, and insulinopenic rats, chronic ICV leptin consistently decreases HGP [150,[152][153][154]. These effects may have something to do with the specific signaling pathways activated by leptin.…”

Butyrate-rich Colonic Microenvironment Is a Relevant Selection Factor for Metabolically Adapted Tumor Cells

“…It was also observed that glutamate was synthesized from butyrate 13 C atoms, indicating that acetyl-CoA from butyrate degradation is also entering Kreb's cycle. RETN is a hormone that represses the uptake of glucose by cells and has been implicated in insulin resistance (23), and its overexpression (as shown here) indicates that butyrate-preselected HCT15 cells prefer to metabolize butyrate rather than glucose. RETN has also been described in throphoblastic cells as being responsible for GLUT1 down-regulation (24) as we saw in HCT15 butyrate-preselected cells.…”