title: 5-HT obesity medication efficacy via POMC activation is maintained during aging.
abstract: 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.
authors: 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.
authors: Luke K
authors: LK
authors: Burke
authors: Barbora
authors: B
authors: Doslikova
authors: Giuseppe
authors: G
authors: D'Agostino
authors: Alastair S
authors: AS
authors: Garfield
authors: Gala
authors: G
authors: Farooq
authors: Denis
authors: D
authors: Burdakov
authors: Malcolm J
authors: MJ
authors: Low
authors: Marcelo
authors: M
authors: Rubinstein
authors: Mark L
authors: ML
authors: Evans
authors: Brian
authors: B
authors: Billups
authors: Lora K
authors: LK
authors: Heisler
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D005260:Female; D005277:Fenfluramine / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005277:Fenfluramine; D011333:Pro-Opiomelanocortin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors