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. 2020 Jan 29;12(528):eaau5956.
doi: 10.1126/scitranslmed.aau5956.

Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes

Geetanjali Sharma  1 , Chelin Hu  2 , Daniela I Staquicini  3   4 , Jonathan L Brigman  5 , Meilian Liu  6   7 , Franck Mauvais-Jarvis  8   9 , Renata Pasqualini  3   4 , Wadih Arap  4   10 , Jeffrey B Arterburn  11 , Helen J Hathaway  2   12 , Eric R Prossnitz  13   7   12
Affiliations

Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes

Geetanjali Sharma et al. Sci Transl Med. .

Erratum in

Abstract

Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein-coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1-treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.

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Conflict of interest statement

Competing interests: E.R.P. is an inventor on U.S. Patent No. 10,251,870 and G.S. and E.R.P. are inventors on U.S. patent No. 10,471,047, both for the therapeutic use of compounds targeting GPER (“Method for treating obesity, diabetes, cardiovascular and kidney diseases by regulating GPR30/GPER”). E.R.P. and J.B.A. are inventors on U.S. Patent Nos. 7,875,721 and 8,487,100 for GPER-selective ligands and imaging agents (“Compounds for binding to ERα/β and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof”). R.P. and W.A are inventors on issued patents related to adipotide (U.S. Patent Nos. 7,452,964, 7,951,362, 8,252,764 and 8,846,859 entitled “Compositions and methods of use of targeting peptides against placenta and adipose tissues”, and U.S. patent No. 8,067,377 entitled “Peptide compositions for targeting adipose tissue”) and are founders of PhageNova Bio, which has optioned intellectual property related to adipotide, an investigational anti-obesity agent. R.P. is the Chief Scientific Officer and a paid consultant for PhageNova Bio. G.S., E.R.P., J.B.A., R.P. and W.A. are entitled to royalties if licensing or commercialization occurs. These arrangements are managed in accordance with established institutional conflict of interest policies. Other authors declare no conflicts of interest.

Figures

Fig. 1.
Fig. 1.. Selective activation of GPER in OVX mice attenuates obesity.
Body weight in OVX mice after treatment with GPER agonist G-1 compared to vehicle (Veh) controls and ovary-intact mice (A) over time and (B) at termination of the study. Images of representative mice are shown in (B). The weight of the perigonadal (C) and perirenal (D) fat pads, circulating cholesterol (E) and uterine wet weight (F) were determined at termination of the study. A, n=5 (Intact) −14 (OVX+Veh, OVX+G-1); B, n=13; C, D, F, n=7: E, n=6). A, two-way ANOVA; *P < 0.05, **P < 0.01, ***P < 0.001 for vehicle treatment vs. ovary intact controls, respectively; #P < 0.05 for G-1 treatment vs. vehicle treatment. B-F, one-way ANOVA with Bonferroni post-hoc test.
Fig. 2.
Fig. 2.. Treatment with GPER-selective agonist G-1 reduces fat content in OVX mice.
(A) Representative DEXA scans, (B) overall body fat content, (C) body fat percentage, (D) lean mass, (E) bone mineral density and (F) bone mineral content in vehicle- and G-1-treated OVX mice compared to ovary-intact animals. Representative anatomical MRI images of the (G) coronal and (I) axial view in different mouse cohorts with quantification of (H) total (from coronal view) and (J) subcutaneous (from axial view) fat content. B-F, n=6; H and J, n=4. All tests one-way ANOVA with Bonferroni post-hoc test.
Fig. 3.
Fig. 3.. GPER activation in OVX mice increases energy expenditure.
(A) Energy expenditure over time (VO2, mL/hr), (B) respiratory exchange ratio over time (VCO2/VO2), (C) oxygen consumption (VO2, total, light and dark phases), (D) food intake and (E) locomotor activity over time and (F) total, light and dark phases, in vehicle- and G-1-treated OVX mice compared to the ovary-intact control animals. A-C, n=6 (Intact) −8 (OVX+Veh, OVX+G-1); D-F, n=4-7. All tests one-way ANOVA with Bonferroni post-hoc test.
Fig. 4.
Fig. 4.. Adipose tissue remodeling in OVX mice treated with GPER-selective agonist G-1.
(A) Perigonadal fat pads (whole mount and H&E stained sections; scale bar, 100 μm) and (B) mean adipocyte area as quantified after H&E staining in (A) (n=5). (C) Gene expression analyses in perigonadal WAT for genes involved in angiogenesis (Hif1a and Vegfa) and mitochondrial biogenesis (Ppargc1a) and fatty acid oxidation (Acox1) (n=6). (D) Gene expression analyses in BAT for genes involved in thermogenesis (Ucp1) and sympathetic innervation (Th) (n=6). All tests one-way ANOVA with Bonferroni post-hoc test.
Fig. 5.
Fig. 5.. G-1 treatment increases mitochondrial gene expression and cellular respiration.
Expression of the mitochondrial genes Ppargc1a, Acaca, Nrf1, Tfam and Acox1 in (A) BAT and (B) skeletal muscle following vehicle or G-1 treatment of OVX mice (n=5–6). (C) Oxygen consumption rate (OCR) of brown preadipocytes under basal conditions (0-16 min) following GPER stimulation for 24 h with 100 nM G-1. * P< 0.001 for G-1-treated cells vs. vehicle control. (D) Basal OCR, maximal OCR, spare respiratory capacity and OCR for ATP production in G-1-treated cells vs. control cells. The results shown in (C) and (D) are representative of three independent experiments with 4 replicates for each condition per experiment as indicated. (A and B) one-way ANOVA with Bonferroni post-hoc test, (C) two-way ANOVA, (D) Mann-Whitney U test.
Fig. 6.
Fig. 6.. GPER agonism attenuates inflammation resulting from OVX.
(A) Systemic concentrations of inflammatory cytokines (n=8). Gene expression of inflammatory markers in (B) perigonadal WAT, (C) liver and (D) skeletal muscle (n=5-6). All tests one-way ANOVA with Bonferroni post-hoc test.
Fig. 7.
Fig. 7.. GPER-selective agonist G-1 improves glucose homeostasis in OVX mice and modulates systemic concentrations of metabolic hormones.
(A, B) Tolerance to glucose (glucose tolerance test, GTT), fasting plasma (C) glucose and (D) insulin, and (E) HOMA-IR in vehicle- and G-1-treated OVX mice compared to ovary-intact mice. For GTT, area under the curve for each individual mouse in A was plotted in B. (F) Concentrations of plasma leptin, insulin, pancreatic polypeptide (PP), C-peptide 2, and glucagon in the fed state. A-E, n=6; F, n=6-8. All tests one-way ANOVA with Bonferroni post-hoc test.
Fig. 8.
Fig. 8.. Activation of GPER by G-1 exerts anti-obesity and anti-diabetic effects in male DIO mice.
(A) Body weights (n=14), (B) plasma cholesterol concentrations (n=6), (C) energy expenditure (n=4), fasting (D) glucose (n=6) and (E) insulin (n=6) concentrations, (F) HOMA-IR (n=6) and (G, H) glucose tolerance (n=8) in DIO male mice treated with vehicle or G-1 compared in male mice fed normal chow (NC). For (D) and (H), area under the curve was determined for each individual mouse in (C) and (G), respectively. All tests one-way ANOVA with Bonferroni post-hoc test.
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