leptin and lorcaserin

Currently, obesity presents one of the biggest health problems. Management strategies for weight reduction in obese individuals include changes in life style such as exercise and diet, behavioral therapy, and pharmacological treatment, and in certain cases surgical intervention. Diet and exercise are best for both prevention and treatment, but both require much discipline and are difficult to maintain. Drug treatment of obesity offer a possible adjunct, but it may only have modest results, limited by side effects; furthermore, the weight lowering effects last only as long as the drug is being taken and, unfortunately, as soon as the administration is stopped, the weight is regained. These strategies should be used in a combination for higher efficacy. Drugs used to induce weight loss have various effects: they increase satiety, reduce the absorption of nutrients or make metabolism faster; but their effect is usually moderate. In the past, several drugs were used in the pharmacological therapy of weight reduction including thyroid hormone, dinitrophenol, amphetamines and their analogues, e.g. fenfluramine, At present, only orlistat is available in the long term treatment (≥ 24 weeks) of obesity as sibutramine and rimonabant were withdrawn form the market. Several new anti-obesity drugs are being tested at present, and liraglutide, a GLP-1 analogue (incretin mimetic), is the most promising one.

Topics: Amides; Anti-Obesity Agents; Anticonvulsants; Antidepressive Agents; Basal Metabolism; Benzazepines; Benzoxazines; Body Mass Index; Bridged Bicyclo Compounds, Heterocyclic; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Combined Modality Therapy; Cyclobutanes; Dexfenfluramine; Fatty Acids; Female; Fenfluramine; Glucagon-Like Peptide 1; Human Growth Hormone; Humans; Intestinal Absorption; Lactones; Leptin; Life Style; Liraglutide; Male; Norepinephrine; Obesity; Obesity, Morbid; Orlistat; Piperidines; Pyrazoles; Pyridines; Receptor, Melanocortin, Type 4; Rimonabant; Satiation; Serotonin; Sodium-Glucose Transport Proteins; Sucrose; Thyroid Hormones

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