Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons

Luke K. Burke, Barbora Doslikova, Giuseppe D'Agostino, Megan Greenwald-Yarnell, Teodora Georgescu, Raffaella Chianese, Pablo B. Martinez de Morentin, Emmanuel Ogunnowo-Bada, Celine Cansell, Lourdes Valencia-Torres, Alastair S. Garfield, John Apergis-Schoute, Daniel D. Lam, John R. Speakman, Marcelo Rubinstein, Malcolm J. Low, Justin J. Rochford, Martin G. Myers, Mark L. Evans, Lora K. Heisler

Research output: Contribution to journalArticle

32 Citations (Scopus)
6 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)245-252
Number of pages8
JournalMolecular Metabolism
Volume5
Issue number3
Early online date22 Jan 2016
DOIs
Publication statusPublished - Mar 2016

Fingerprint

Pro-Opiomelanocortin
Sex Characteristics
Energy Metabolism
Obesity
Neurons
Serotonin Receptors
Brown Adipose Tissue
Body Weight
Appetite
Peptides
Arcuate Nucleus of Hypothalamus
Morbid Obesity
Brain
Feeding Behavior
Energy Intake
Insulin Resistance
Primary Health Care
Serotonin
Homeostasis
Eating

Keywords

  • 5-HT2c receptor
  • Brown adipose tissue
  • Energy expenditure
  • Hyperinsulinemia
  • Hypothalamus
  • Obesity
  • Pro-opiomelanocortin (Pomc)
  • Sexual dimorphism

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. / Burke, Luke K.; Doslikova, Barbora; D'Agostino, Giuseppe; Greenwald-Yarnell, Megan; Georgescu, Teodora; Chianese, Raffaella; Martinez de Morentin, Pablo B.; Ogunnowo-Bada, Emmanuel; Cansell, Celine; Valencia-Torres, Lourdes; Garfield, Alastair S.; Apergis-Schoute, John; Lam, Daniel D.; Speakman, John R.; Rubinstein, Marcelo; Low, Malcolm J.; Rochford, Justin J.; Myers, Martin G.; Evans, Mark L.; Heisler, Lora K.

In: Molecular Metabolism, Vol. 5, No. 3, 03.2016, p. 245-252.

Research output: Contribution to journalArticle

Burke, LK, Doslikova, B, D'Agostino, G, Greenwald-Yarnell, M, Georgescu, T, Chianese, R, Martinez de Morentin, PB, Ogunnowo-Bada, E, Cansell, C, Valencia-Torres, L, Garfield, AS, Apergis-Schoute, J, Lam, DD, Speakman, JR, Rubinstein, M, Low, MJ, Rochford, JJ, Myers, MG, Evans, ML & Heisler, LK 2016, 'Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons' Molecular Metabolism, vol. 5, no. 3, pp. 245-252. https://doi.org/10.1016/j.molmet.2016.01.005
Burke, Luke K. ; Doslikova, Barbora ; D'Agostino, Giuseppe ; Greenwald-Yarnell, Megan ; Georgescu, Teodora ; Chianese, Raffaella ; Martinez de Morentin, Pablo B. ; Ogunnowo-Bada, Emmanuel ; Cansell, Celine ; Valencia-Torres, Lourdes ; Garfield, Alastair S. ; Apergis-Schoute, John ; Lam, Daniel D. ; Speakman, John R. ; Rubinstein, Marcelo ; Low, Malcolm J. ; Rochford, Justin J. ; Myers, Martin G. ; Evans, Mark L. ; Heisler, Lora K. / Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. In: Molecular Metabolism. 2016 ; Vol. 5, No. 3. pp. 245-252.
@article{e61be285b8bd46b3ace7c1a92c70e26d,
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.",
keywords = "5-HT2c receptor, Brown adipose tissue, Energy expenditure, Hyperinsulinemia, Hypothalamus, Obesity, Pro-opiomelanocortin (Pomc), Sexual dimorphism",
author = "Burke, {Luke K.} and Barbora Doslikova and Giuseppe D'Agostino and Megan Greenwald-Yarnell and Teodora Georgescu and Raffaella Chianese and {Martinez de Morentin}, {Pablo B.} and Emmanuel Ogunnowo-Bada and Celine Cansell and Lourdes Valencia-Torres and Garfield, {Alastair S.} and John Apergis-Schoute and Lam, {Daniel D.} and Speakman, {John R.} and Marcelo Rubinstein and Low, {Malcolm J.} and Rochford, {Justin J.} and Myers, {Martin G.} and Evans, {Mark L.} and Heisler, {Lora K.}",
note = "Acknowledgments Work was supported by the Wellcome Trust (WT098012; WT081713) and Biotechnology and Biological Sciences Research Council (BB/K001418/1) to LKH, Wellcome Trust (093566/Z/10/A) to LKB/LKH, the Diabetes UK (13/0004680) to MLE, the Genomics/Transcriptomics core, Disease Model Core, Bespoke Mouse Models, Imaging, Proteomics Wellcome Trust Strategic Award [100574/Z/12/Z] and Genomics/Transcriptomics Core Facilities, Disease Model Core, CBAL MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5] to LKH, MLE, BD and LKB, the Neuroscience Graduate Program, University of Michigan to MG-Y, the National Institute of Health (DK066604) to MJL and (DK068400) to MJL and MR, and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The authors would like to thank Dr Samuel Virtue for technical training in BAT lipid accumulation quantification.",
year = "2016",
month = "3",
doi = "10.1016/j.molmet.2016.01.005",
language = "English",
volume = "5",
pages = "245--252",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
number = "3",

}

TY - JOUR

T1 - Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons

AU - Burke, Luke K.

AU - Doslikova, Barbora

AU - D'Agostino, Giuseppe

AU - Greenwald-Yarnell, Megan

AU - Georgescu, Teodora

AU - Chianese, Raffaella

AU - Martinez de Morentin, Pablo B.

AU - Ogunnowo-Bada, Emmanuel

AU - Cansell, Celine

AU - Valencia-Torres, Lourdes

AU - Garfield, Alastair S.

AU - Apergis-Schoute, John

AU - Lam, Daniel D.

AU - Speakman, John R.

AU - Rubinstein, Marcelo

AU - Low, Malcolm J.

AU - Rochford, Justin J.

AU - Myers, Martin G.

AU - Evans, Mark L.

AU - Heisler, Lora K.

N1 - Acknowledgments Work was supported by the Wellcome Trust (WT098012; WT081713) and Biotechnology and Biological Sciences Research Council (BB/K001418/1) to LKH, Wellcome Trust (093566/Z/10/A) to LKB/LKH, the Diabetes UK (13/0004680) to MLE, the Genomics/Transcriptomics core, Disease Model Core, Bespoke Mouse Models, Imaging, Proteomics Wellcome Trust Strategic Award [100574/Z/12/Z] and Genomics/Transcriptomics Core Facilities, Disease Model Core, CBAL MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5] to LKH, MLE, BD and LKB, the Neuroscience Graduate Program, University of Michigan to MG-Y, the National Institute of Health (DK066604) to MJL and (DK068400) to MJL and MR, and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The authors would like to thank Dr Samuel Virtue for technical training in BAT lipid accumulation quantification.

PY - 2016/3

Y1 - 2016/3

N2 - 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.

AB - 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.

KW - 5-HT2c receptor

KW - Brown adipose tissue

KW - Energy expenditure

KW - Hyperinsulinemia

KW - Hypothalamus

KW - Obesity

KW - Pro-opiomelanocortin (Pomc)

KW - Sexual dimorphism

UR - http://www.scopus.com/inward/record.url?scp=84959140900&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2016.01.005

DO - 10.1016/j.molmet.2016.01.005

M3 - Article

VL - 5

SP - 245

EP - 252

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

IS - 3

ER -