We have observed late-onset obesity in mutant mice lacking the serotonin 5-HT 2C receptor. Despite chronically elevated food intake, young adult mutants exhibit neither elevated adiposity nor altered glucose or fat homeostasis. However, obesity subsequently develops after 6 months of age without increases in their level of hyperphagia. In this study, we investigated determinants of energy expenditure in 5-HT 2C receptor mutant mice. Young adult mutants displayed patterns of elevated activity levels that were enhanced by fasting and tightly associated with repeated visits to a food source. Surprisingly, subsequent obesity development occurred despite persisting locomotor hyperactivity and without age-related declines in resting metabolic rate. Rather, substantial reductions in the energy cost of locomotor activity (LA) were observed in 5-HT 2C receptor mutant mice. Moreover, both mutant and wild-type mice displayed age-related declines in the energy cost of LA, indicating that this process may be regulated by both aging and serotonergic signaling. These results indicate that a mutation of the 5-HT 2C receptor gene (htr2c) increases LA, which contributes to the maintenance of normal body composition in young adult mutants despite their hyperphagia. Moreover, age-dependent reductions in the energy cost of physical activity could contribute to the subsequent development of late-onset obesity in 5-HT 2C receptor mutant mice. Diabetes 52: 315-320, 2003 M ultiple lines of evidence indicate that the monoamine serotonin (5-hydroxytryptamine [5-HT]) exerts powerful influences on feeding behavior (1,2). Treatments that enhance brain serotonergic transmission, such as the prototypical appetite suppressant fenfluramine, serotonin reuptake blockers, the serotonin precursor L-tryptophan, and nonspecific 5-HT receptor agonists, suppress food intake. Conversely, treatments that reduce serotonergic neural activity, such as intraventricular injections of the serotonergic neurotoxin 5,7-dihydroxytryptamine and lesions of the serotonergic raphe B8 cell group, produce chronic hyperphagia and weight gain. Several lines of evidence implicate the 5-HT 2C receptor in the anorectic effects of brain serotonergic systems (1-4). For example, the nonselective 5-HT receptor agonist m-chlorophenylpiperazine and the fenfluramine metabolite norfenfluramine have appetite suppressant actions that are blocked by 5-HT 2C receptor antagonist compounds.The 5-HT 2C receptor is expressed in many brain regions, and its expression is restricted to the central nervous system (5,6). To investigate the functional roles of this receptor subtype, we have generated a line of mice bearing a mutation of the htr2c gene. These animals display hyperphagia, reduced sensitivity to the anorectic effects of m-chlorophenylpiperazine and dexfenfluramine, enhanced susceptibility to type 2 diabetes, and a late-onset obesity syndrome (2,7,8). Despite their chronically elevated food intake, young adult mutants exhibit neither elevated adiposity nor alterations in plasma levels...

The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT 2C R) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT 2C Rs produces marked alterations in the activity and functional output of this pathway. 5-HT 2C R mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of D-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D 1 receptor agonist SKF 81297. Differences in DSt D 1 or D 2 receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT 2C Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.

and A substantial literature is consistent with the hypothesis that systemic AMPH reduces appetite by release of Howard Hughes Medical Institute University of Washington catecholamines within the perifornical lateral hypothalamus (pfLH) (Baptista et al., 1993; Chen et al., 2001; Kuo,

Neural mechanisms underlying the regulation of ingestive behavior and energy balance are well conserved among mammals. Many neural pathways, each reflecting the function of many genes, interact to regulate these processes. Systematic genetic perturbations are not feasible in humans—the examination of gene functions relevant to feeding regulation must be performed in other species. Many advances in this field have been made through molecular genetic studies of mice, the most genetically tractable of mammalian species. The relevance of mouse ingestive behavior to the mechanisms underlying the regulation of feeding in humans is discussed. Approaches for evaluating the contribution of genes to the regulation of energy balance and to the actions of anorectic drugs are described in the context of studies focused on a line of mice lacking the serotonin 5-HT2C receptor subtype. These animals display reduced responsiveness to serotonergic anorexic drugs and a late-onset obesity syndrome associated with features reminiscent of common forms of human obesity. Developmental studies of energy balance uncovered a novel age-dependent physiological process that may contribute generally to the predisposition of humans and other mammals to accumulate fat stores during “middle-age.” These findings are presented to illustrate considerations in the use of mouse molecular genetic technologies to investigate genetic influences on ingestive behavior and energy balance.