title: Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons.
abstract: OBJECTIVE
  Obesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified.
  
  
  METHODS
  Given that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT 2C R (CRE) mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable Pomc (NEO) mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight.
  
  
  RESULTS
  Here we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity.
  
  
  CONCLUSIONS
  These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual.
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK; Department of Medicine and Institute of Metabolic Science, University of Cambridge, Wellcome Trust/Medical Research Council, Cambridge, UK; Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Luke K
authors.initials: LK
authors.lastname: Burke
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Barbora
authors.initials: B
authors.lastname: Doslikova
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK; Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Greenwald-Yarnell
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Teodora
authors.initials: T
authors.lastname: Georgescu
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Chianese
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Pablo B
authors.initials: PB
authors.lastname: Martinez de Morentin
authors.affiliation: Department of Medicine and Institute of Metabolic Science, University of Cambridge, Wellcome Trust/Medical Research Council, Cambridge, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Ogunnowo-Bada
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Celine
authors.initials: C
authors.lastname: Cansell
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK; Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valencia-Torres
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Alastair S
authors.initials: AS
authors.lastname: Garfield
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Apergis-Schoute
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Lam
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: John R
authors.initials: JR
authors.lastname: Speakman
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428, Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rubinstein
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Low
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Rochford
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: Department of Medicine and Institute of Metabolic Science, University of Cambridge, Wellcome Trust/Medical Research Council, Cambridge, UK. Electronic address: mle24@cam.ac.uk.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Evans
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK. Electronic address: lora.heisler@abdn.ac.uk.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
keywords: 5-HT2c receptor; Brown adipose tissue; Energy expenditure; Hyperinsulinemia; Hypothalamus; Obesity; Pro-opiomelanocortin (Pomc); Sexual dimorphism