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. 2014 Jun;66(1):196-207.
doi: 10.1016/j.yhbeh.2014.02.004. Epub 2014 Feb 18.

Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis

Kathryn E Davis  1 , Elizabeth J Carstens  2 , Boman G Irani  3 , Lana M Gent  3 , Lisa M Hahner  3 , Deborah J Clegg  4
Affiliations

Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis

Kathryn E Davis et al. Horm Behav. 2014 Jun.

Abstract

This article is part of a Special Issue "Energy Balance". The classical estrogen receptors, estrogen receptor-α and estrogen receptor-β are well established in the regulation of body weight and energy homeostasis in both male and female mice, whereas, the role for G protein-coupled estrogen receptor 1 (GPER) as a modulator of energy homeostasis remains controversial. This study sought to determine whether gene deletion of GPER (GPER KO) alters body weight, body adiposity, food intake, and energy homeostasis in both males and females. Male mice lacking GPER developed moderate obesity and larger adipocyte size beginning at 8 weeks of age, with significant reductions in energy expenditure, but not food intake or adipocyte number. Female GPER KO mice developed increased body weight relative to WT females a full 6 weeks later than the male GPER KO mice. Female GPER KO mice also had reductions in energy expenditure, but no significant increases in body fat content. Consistent with their decrease in energy expenditure, GPER KO males and females showed significant reductions in two brown fat thermogenic proteins. GPER KO females, prior to their divergence in body weight, were less sensitive than WT females to the feeding-inhibitory effects of leptin and CCK. Additionally, body weight was not as modulated by ovariectomy or estradiol replacement in GPER KO mice. Estradiol treatment activated phosphorylated extracellular signal-regulated kinase (pERK) in WT but not GPER KO females. For the first time, GPER expression was found in the adipocyte but not the stromal fraction of adipose tissue. Together, these results provide new information elucidating a sexual dimorphism in GPER function in the development of postpubertal energy balance.

Keywords: Adiposity; Cholecystokinin; Estrogen receptor-α; G protein coupled receptor 30; Leptin.

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Figures

Figure 1
Figure 1
Body weight, food intake, and energy expenditure of GPER KO mice. A. Weekly body weights of male WT and GPER KO mice. B. Weekly body weights of female WT and GPER KO mice. C. Average daily food intake in male and female WT and GPER KO mice tracked at 13 weeks. D. Fat mass measured by NMR in 13 week old male and female WT and GPER KO mice. E. Energy expenditure was measured and represented by average VO2 for 10 week old male WT and GPER KO mice. F. Energy expenditure was measured and represented by average VO2 for 10 week old female WT and GPER KO mice. All data are expressed as mean ± SEM and n=12-19 per group. Values significantly different from sex- and age-matched WT controls are designated by asterisks above the column. * P<0.05.
Figure 2
Figure 2
Circulating inflammatory factors and adipokines. A. Circulating SAA3 levels measured from serum in male and female 13 week old WT and GPER KO mice. B. Circulating adiponectin levels measured from serum in male and female 13 week old WT and GPER KO mice. All data are expressed as mean ± SEM and n=8-10 per group. Values significantly different from sex- and age-matched WT controls are designated by asterisks above the column. * P<0.05.
Figure 3
Figure 3
White adipose morphology and GPER expression in adipose tissues. A. Average adipocyte area as measures from H&E sections from gonadal/visceral adipose tissues in 13 week old male and female WT and GPER KO mice. B. Representative H&E sections of adipose tissues used to calculate adipocyte area from male, female WT and GPER KO mice. C. Expression of GPER in whole adipose tissue, isolated adipocytes, and the stromal vascular (SV) fraction in 13 week old male and female WT mice. All data are expressed as mean ± SEM and n=8-10 per group. Values significantly different from sex- and age-matched WT controls are designated by asterisks above the column. * P<0.05.
Figure 4
Figure 4
Brown adipose tissue. A. Representative H&E sections of brown adipose tissues from 13 week old WT and GPER KO male and female mice. B. Gene expression of brown adipose tissue genes involved in lipid accumulation and energy expenditure in 13 week old male WT and GPER KO mice. C. Gene expression of brown adipose tissue genes involved in lipid accumulation and energy expenditure in 13 week old female WT and GPER KO mice. Uncoupling protein-1 (UCP1), Peroxisome proliferator activated receptor gamma (PPARg), PPARg coactivator-1 alpha (PGC-1a), beta-3 adrenergic receptor (b3-AdR), PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16). All data are expressed as mean ± SEM and n=8-10 per group. Values significantly different from sex- and age-matched WT controls are designated by asterisks above the column. * P<0.05.
Figure 5
Figure 5
Expression of other ERs and effects of GPER on leptin and CCK sensitivity. A. Basal medial hypothalamic expression of ERα in 13 week old male and female WT and GPER KO mice. B. Basal medial hypothalamic expression of ERβ in 13 week old male and female WT and GPER KO mice. C. Average food intake of 13 week old male WT and GPER KO mice 4 and 24 hours after leptin administration. D. Average food intake of 13 week old female male WT and GPER KO mice 4 and 24 hours after leptin administration. E. Average food intake of 14 week old male WT and GPER KO mice 30 min after CCK administration. F. Average food intake of 14 week old female WT and GPER KO mice 30 min after CCK administration. All data are expressed as mean ± SEM and n=8-10 per group. Values significantly different from sex- and age-matched WT controls are designated by asterisks above the column. * P<0.05.
Figure 6
Figure 6
The effects of 17β-estradiol on body weight, composition, adipocyte morphology and glucose homeostasis in OVX WT and GPER KO females. A. Daily body weight change after OVX in WT mice treated with vehicle or 17β-estradiol. B. Body weight change after OVX in GPER KO mice treated with vehicle or 17β-estradiol. C. Fat mass in 14 week old OVX WT and GPER KO treated with vehicle or 17β-estradiol. D. Oral glucose tolerance test in 13 week old OVX WT mice treated with vehicle or 17β-estradiol. E. Oral glucose tolerance test in 13 week old OVX GPER KO mice treated with vehicle or 17β-estradiol. F. Average adipocyte area as measures from H&E sections from visceral adipose tissues in 14 week old OVX WT and GPER KO mice treated with vehicle or 17β-estradiol. G. Representative H&E sections of adipose tissues measured in F. All data are expressed as mean ± SEM and n=8-12 per group. *P<0.05 compared with vehicle treatment.
Figure 7
Figure 7
17β-estradiol induced phosphorylation of ERK in the basal medial hypothalamus in WT and GPER KO OVX females. A single i3vt injection of 0.05 μg/μl 17β-estradiol increased pErk 1/2 in OVX WT but not OVX GPER KO females (Fig. 7). All data are expressed as mean ± SEM and n=5 per group. *P<0.05 compared with vehicle treatment.
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References

    1. Bellefontaine N, Elias CF. Minireview: Metabolic Control of the Reproductive Physiology: insights from genetic mouse models. Hormones and Behavior. 2014 DOI: - PMC - PubMed
    1. Ropero AB, Alonso-Magdalena P, Quesada I, et al. The role of estrogen receptors in the control of energy and glucose homeostasis. Steroids. 2008;73:874–879. - PubMed
    1. Brown LM, Clegg DJ. Central effects of estradiol in the regulation of food intake, body weight, and adiposity. J Steroid Biochem Mol Biol. 2010;122:65–73. - PMC - PubMed
    1. Shi H, Seeley RJ, Clegg DJ. Sexual differences in the control of energy homeostasis. Front Neuroendocrinol. 2009;30:396–404. - PMC - PubMed
    1. Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev. 2013;34:309–338. - PMC - PubMed

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