lorcaserin and Insulin-Resistance

The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT. Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control.. Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R. These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

Topics: Animals; Benzazepines; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Energy Metabolism; Glucose; Glucose Tolerance Test; Homeostasis; Humans; Insulin Resistance; Melanocortins; Mice; Mice, Transgenic; Obesity; Receptor, Serotonin, 5-HT2C; Receptors, Melanocortin; Weight Loss

The molecular mechanisms underlying acute leptin and serotonin 2C receptor-induced hypophagia remain unclear. Here, we show that neuronal and pro-opiomelanocortin (Pomc)-specific loss of transient receptor potential cation 5 (TrpC5) subunits is sufficient to decrease energy expenditure and increase food intake resulting in elevated body weight. Deficiency of Trpc5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr) agonists. The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons. We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons. Together, our results link TrpC5 subunits in the brain with leptin- and serotonin 2C receptor-dependent changes in neuronal activity, as well as energy balance, feeding behavior, and glucose metabolism.

Topics: Animals; Appetite Depressants; Benzazepines; Body Weight; Eating; Energy Metabolism; Glucose; Glucose Tolerance Test; Insulin Resistance; Leptin; Male; Membrane Potentials; Mice; Mice, Knockout; Neurons; Patch-Clamp Techniques; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Tamoxifen; TRPC Cation Channels

Obesity, generally linked to hyperlipidemia, has been occurring of late with distressing alarm and has now become a global phenomenon casting a huge economic burden on the health care system of countries around the world. The present study investigated the effects of gingerol over 30 days on the changes in HFD-induced obese rats in marker enzymes of lipid metabolism such as fatty-acid synthase (FAS), Acetyl CoA Carboxylase (ACC), Carnitine Palmitoyl Transferase-1(CPT-1), HMG co-A Reductase (HMGR), Lecithin Choline Acyl Transferase (LCAT) and Lipoprotein Lipase (LPL) and inflammatory markers (TNF-α and IL-6). The rats were treated orally with gingerol (75 mg kg(-1)) once daily for 30 days with a lorcaserin-treated group (10 mg kg(-1)) included for comparison. Changes in body weight, glucose, insulin resistance and expressions of lipid marker enzymes and inflammatory markers in tissues were observed in experimental rats. The administration of gingerol resulted in a significant reduction in body weight gain, glucose and insulin levels, and insulin resistance, which altered the activity, expressions of lipid marker enzymes and inflammatory markers. It showed that gingerol had significantly altered these parameters when compared with HFD control rats. This study confirms that gingerol prevents HFD-induced hyperlipidemia by modulating the expression of enzymes important to cholesterol metabolism.

Topics: Animals; Benzazepines; Biomarkers; Body Weight; Catechols; Diet, High-Fat; Fatty Alcohols; Gene Expression Regulation, Enzymologic; Insulin Resistance; Interleukin-6; Lipid Metabolism; Male; Obesity; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha