clozapine-n-oxide and Body-Weight

Parasympathetic nervous system (PNS) innervates with several peripheral organs such as liver, pancreas and regulates energy metabolism. However, the direct role of PNS on food intake has been poorly understood. In the present study, we investigated the role of parasympathetic nervous system in regulation of feeding by chemogenetic methods. Adeno associated virus carrying DREADD (designer receptors exclusively activated by designer drugs) infused into the target brain region by stereotaxic surgery. The stimulatory hM3Dq or inhibitory hM4Di DREADD was over-expressed in selective population of dorsal motor nucleus of the vagus (DMV) neurons by Cre-recombinase-dependent manners. Activation of parasympathetic neuron by intraperitoneal injection of the M3-muscarinic receptor ligand clozapine-N-oxide (CNO) (1 mg/kg) suppressed food intake and resulted in body weight loss in ChAT-Cre mice. Parasympathetic neurons activation resulted in improved glucose tolerance while inhibition of the neurons resulted in impaired glucose tolerance. Stimulation of parasympathetic nervous system by injection of CNO (1 mg/kg) increased oxygen consumption and energy expenditure. Within the hypothalamus, in the arcuate nucleus (ARC) changed AGRP/POMC neurons. These results suggest that direct activation of parasympathetic nervous system decreases food intake and body weight with improved glucose tolerance.

Topics: Animals; Body Weight; Clozapine; Dependovirus; Eating; Energy Metabolism; Feeding Behavior; Hypothalamus; Mice; Mice, Transgenic; Neurons; Parasympathetic Nervous System; Vagus Nerve

Overeating is a serious issue in modern society, causing many health problems, including obesity. Although the hypothalamus has been previously identified as the key brain structure that regulates body weight homeostasis, the downstream pathways and non-canonical neural circuitry involved in feeding behavior remain largely uncharacterized. Here, we discover that suppressing the activity of GABAergic cells in the anterior ventrolateral periaqueductal gray (vlPAG), whether directly or through long-projection GABAergic inputs from either the bed nucleus of the stria terminalis (BNST) or the lateral hypothalamus (LH), is sufficient to promptly induce feeding behavior in well-fed mice. In contrast, optogenetic activation of these cells interrupts food intake in starved mice. Long-term chemogenetic manipulation of vlPAG GABAergic cell activity elicits a corresponding change in mouse body weight. Our studies reveal distinct midbrain GABAergic pathways and highlight an important role of GABAergic cells in the anterior vlPAG in feeding behavior.

Topics: Animals; Antipsychotic Agents; Body Weight; Central Amygdaloid Nucleus; Clozapine; Feeding Behavior; GABA-A Receptor Agonists; GABAergic Neurons; Hypothalamic Area, Lateral; Mice; Muscimol; Neural Pathways; Optogenetics; Periaqueductal Gray; Septal Nuclei

Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRP

Topics: Adenomatous Polyposis Coli Protein; Animals; Anorexia; Behavior, Animal; Body Weight; Cachexia; Calcitonin Gene-Related Peptide; Carcinoma, Lewis Lung; Clozapine; Energy Metabolism; Female; Illness Behavior; Male; Metalloendopeptidases; Mice; Mice, Transgenic; Neoplasms; Parabrachial Nucleus; Tetanus Toxin; Tumor Cells, Cultured