Loss of Nuclear and Membrane Estrogen Receptor-α Differentially Impairs Insulin Secretion and Action in Male and Female Mice - PubMed (original) (raw)

. 2019 Mar;68(3):490-501.

doi: 10.2337/db18-0293. Epub 2018 Oct 10.

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Loss of Nuclear and Membrane Estrogen Receptor-α Differentially Impairs Insulin Secretion and Action in Male and Female Mice

Camille Allard et al. Diabetes. 2019 Mar.

Abstract

Estrogens favor glucose homeostasis primarily through the estrogen receptor-α (ERα), but the respective importance of nuclear ERα (NOER) and membrane ERα (MOER) pools to glucose homeostasis are unknown. We studied glucose homeostasis, insulin secretion, and insulin sensitivity in male and female mice expressing either the NOER or the MOER. Male and female MOER mice exhibited fasting and fed hyperglycemia and glucose intolerance. Female MOER mice displayed impaired central insulin signaling associated with hyperinsulinemia and insulin resistance due to unrestrained hepatic gluconeogenesis, without alterations in glucose-stimulated insulin secretion (GSIS). In contrast, male MOER mice did not exhibit detectable insulin resistance, but showed impaired GSIS associated with reduced brain glucose sensing. Female NOER mice exhibited milder hepatic insulin resistance and glucose intolerance. In conclusion, nuclear ERα signaling is predominant in maintaining glucose homeostasis in mice of both sexes. Lack of nuclear ERα alters the central control of insulin sensitivity in females and predominantly impairs the central regulation of insulin secretion in males.

© 2018 by the American Diabetes Association.

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Figures

Figure 1

Figure 1

Female MOER mice are hyperglycemic and glucose intolerant. A: The control (CTRL) mice express NOER and MOER. Global ERαKO mice lack ERα. NOER mice exhibit a mutation of the ERα palmitoylation site, leading to exclusive ERα nuclear location. MOER mice are ERαKO mice re-expressing the human ERα ligand-binding domain selectively at the membrane. Random-fed (B) and fasting blood glucose (C), random-fed (D) and fasting plasma insulin (E) levels, and blood glucose and calculated area under the curve (AUC, inset) (F) during a GTT (i.p. GTT, 2 g/kg) in 6-month-old female MOER and NOER mice with their respective CTRL littermates. Data correspond to the mean ± SEM (n = 6–23). *P < 0.05, ***P < 0.001.

Figure 2

Figure 2

Male MOER mice are hyperglycemic and glucose intolerant. Random-fed (A) and fasting blood glucose (B), random-fed (C) and fasting plasma insulin (D) levels, and blood glucose and calculated area under the curve (AUC, inset) (E) during a GTT (i.p. GTT, 2 g/kg) in 6-month-old male MOER and NOER mice with their respective control (CTRL) littermates. Data correspond to the mean ± SEM (n = 6–25). *P < 0.05, **P < 0.01. AUC, area under the curve.

Figure 3

Figure 3

Female MOER mice exhibit hepatic insulin resistance. Blood glucose level during an ITT (i.p. ITT) in 6-month-old female mice (0.5–0.75 units/kg) (A) and male (0.75–1.25 units/kg) MOER and NOER mice (B) with their respective control (CTRL) littermates. Data correspond to the mean ± SEM (n = 4–19). Body weight of 6-month-old female (C) and male (E) NOER and MOER mice with their respective control (CTRL) littermates. Adipose tissue weight in the indicated fat pads of 6-month-old female (D) and male (F) NOER and MOER mice with their respective CTRL littermates. Data correspond to the mean ± SEM (n = 6–24). AUC, area under the curve; iBAT, inguinal brown adipose tissue. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4

Figure 4

Female MOER mice exhibit central insulin resistance. GIR (left panel) and corresponding area under the curve (AUC) (right panel) calculated during a hyperinsulinemic-euglycemic clamp in female control (CTRL) and MOER mice (A) and female CTRL and NOER mice (D). Glucose turnover (Rt, mg/kg/min) in CTRL and MOER (B) and CTRL and NOER (E) female mice. EndoRa (in mg/kg/min) in female CTRL and MOER (C) and CTRL and NOER (F) mice. Clamp was performed in 6-month-old mice (n = 5–6). G: Blood glucose and calculated AUC (inset) during a PTT (i.p. PTT, 2 g/kg) in female CTRL and MOER mice (n = 4–6). H: Protein expression for pAkt (S473), pAkt (T308), and total Akt in liver from female MOER mice at the end of the 2-h clamp were analyzed by Western blotting. Quantification by densitometry is shown in adjacent bar graphs (n = 5–6). I: Hepatic IL-6 mRNA expression quantified by quantitative PCR in female mice at the end of the 2-h clamp (n = 5–6). J: Protein expression for pSTAT3 (Y701) and STAT3 in liver from female MOER mice at the end of the 2-h clamp were analyzed as in H. K: Protein expression for pAkt (S473)/Akt in hippocampus from female CTRL and MOER at the end of 3 h of intracerebroventricular perfusion of vehicle (VEH) or insulin (INS). Quantification by densitometry is shown in adjacent bar graphs (n = 2–3). Protein expression for pSTAT3/STAT3 (L) and pAkt (S473)/Akt and pAkt (T308)/Akt (M) in liver from female CTRL and MOER mice at the end of 3 h of intracerebroventricular perfusion of vehicle or insulin analyzed as in L (n = 4–6). Data correspond to mean values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 5

Figure 5

Male MOER mice exhibit reduced first-phase insulin secretion in vivo. A: Plasma insulin (left panel) and calculated area under the curve (AUC) (right panel) during an in vivo i.p. GSIS test (GSIS, 3 g/kg) in male control (CTRL) and MOER mice (n = 14–17). B: Representative pictures of pancreatic islets stained for insulin (red) and calculated β-cell mass (mg, n = 6–7) in mice from A. Scale bar, 100 μm. C: Pancreatic insulin content in male CTRL and MOER mice (n = 6). D: Plasma insulin levels 30 min after an i.p. injection of glucose (2 g/kg), showing the second-phase insulin secretion in male CTRL and MOER mice (n = 6–16). In vitro GSIS in static incubation in cultured islets isolated from MOER and CTRL male mice without E2 (E) or with E2 (G) (10−8 mol/L). F and H: Insulin content of islets from E and G (n = 8–19 islet batches from three to seven different animals). Blood glucose (I) and plasma insulin (J) levels during a brain glucose-sensing test (25 mg/kg glucose) in male CTRL and MOER (n = 10–11, five independent experiments). K: Plasma insulin (left panel) and calculated AUC (right panel) during an in vivo GSIS (3 g/kg) in female CTRL and MOER mice (n = 7–8). L: Representative pictures of female CTRL and MOER pancreatic islets stained for insulin (red) and calculated β-cell mass (in mg; n = 4). Scale bar, 100 μm. M: Pancreatic insulin content in female CTRL and MOER mice (n = 3–7). N: Plasma insulin levels 30 min after an i.p. injection of glucose (2 g/kg), showing the second phase of insulin secretion in female CTRL and MOER mice (n = 7–18). Data were collected from 6- to 8-month-old mice and correspond to mean values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 6

Figure 6

Sex differences in NOER and MOER effects on glucose homeostasis. In female mice, NOER signaling in the brain promotes the suppression of HGP via a brain-liver IL-6-STAT3 axis. MOER also participates in control of HGP. In male mice, NOER action in the brain favors glucose-stimulated first-phase insulin secretion.

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