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Endocrinology. 2014 Oct;155(10):3732-8. doi: 10.1210/en.2014-1223. Epub 2014 Jul 22.

5-HT obesity medication efficacy via POMC activation is maintained during aging.

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Department of Pharmacology (L.K.B., B.D., G.D., A.S.G., G.F., D.B., B.B., L.K.H.) and Wellcome Trust/Medical Research Council Institute of Metabolic Science (M.L.E.), University of Cambridge, Cambridge, CB2 0QQ, United Kingdom; Rowett Institute of Nutrition and Health (G.D., L.K.H.), University of Aberdeen, Aberdeen, AB21 9SB, United Kingdom; Department of Molecular and Integrative Physiology (M.J.L., M.R.), University of Michigan Medical School, Ann Arbor, Michigan 48105; and Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (M.R.), Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina.


The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population.

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