Reproductive tissues maintain insulin sensitivity in diet-induced obesity - PubMed (original) (raw)

Comparative Study

Reproductive tissues maintain insulin sensitivity in diet-induced obesity

Sheng Wu et al. Diabetes. 2012 Jan.

Abstract

Reproductive dysfunction is associated with obesity. We previously showed that female mice with diet-induced obesity (DIO) exhibit infertility and thus serve as a model of human polycystic ovary syndrome (PCOS). We postulated that differential insulin signaling of tissues leads to reproductive dysfunction; therefore, a comparison of insulin signaling in reproductive tissues and energy storage tissues was performed. Pituitary-specific insulin receptor knockout mice were used as controls. High-fat diet-induced stress, which leads to insulin resistance, was also investigated by assaying macrophage infiltration and phosphorylated Jun NH(2)-terminal kinase (pJNK) signaling. In lean mice, reproductive tissues exhibited reduced sensitivity to insulin compared with peripheral metabolic tissues. However, in obese mice, where metabolic tissues exhibited insulin resistance, the pituitary and ovary maintained insulin sensitivity. Pituitaries responded to insulin through insulin receptor substrate (IRS)2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin. Macrophage infiltration and pJNK signaling were not increased in the pituitary or ovary of lean mice relative to DIO mice. The lack of inflammation and cytokine signaling in the pituitary and ovary in DIO mice compared with lean mice may be one of the reasons that these tissues remained insulin sensitive. Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS.

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Figures

FIG. 1.

FIG. 1.

WT lean and DIO female mice were fasted overnight, and biochemical data are shown. A: Insulin. B: Leptin. C: Glucagon. D: IGF-I. E: Glucose tolerance test (2 g/kg i.p.

d

-glucose injected; glucose levels measured at different time points). n = 4–6/group. *,a,bSignificant differences (P < 0.05). NS, nonsignificant. GTT, glucose tolerance test.

FIG. 2.

FIG. 2.

Time course of response to different doses of insulin in overnight-fasted lean female mice. Glucose was measured at 0, 10, 30, and 45 min. No significant decline in glucose levels was observed at any dose at 10 min. (A high-quality color representation of this figure is available in the online issue.)

FIG. 3.

FIG. 3.

Fasted lean female mice were injected with saline or 0.5, 1, or 1.5 units/kg body wt insulin, and total AKT, pAKT, and pERK1/2 levels were measured in tissue homogenates using the Luminex analyzer. pAKT and pERK values are displayed relative to those of saline-injected mice and are corrected for total AKT. Total AKT values are expressed as relative light units. Different letters indicate significant differences between groups (P < 0.05). A and B: Liver. C and D: Muscle. E and F: Pituitary. G and H: Ovary. I and J: Hypothalamus. K: 0.5 units–total AKT. L: 1 unit–total AKT. M: 1.5 units–total AKT. NS, nonsignificant. pit, pituitary. hypo, hypothalamus.

FIG. 4.

FIG. 4.

Western blot identifies differences in insulin-signaling pathways between reproductive tissues and the energy storage tissues. A: Female lean mice were fasted overnight and injected with insulin (1.5 units/kg body wt). B: pAKT levels of lean and DIO female mice were compared before or after insulin stimulation. (A high-quality color representation of this figure is available in the online issue.)

FIG. 5.

FIG. 5.

Luminex analysis of pAKT signaling after overnight-fasted mice were injected with insulin. WT lean, WT DIO, and PITIRKO-DIO mice were compared with regard to reproductive and energy storage tissues. n = 4–8/group. Bars with different letters are significantly different (P < 0.05). A: Pituitary. B: Ovary. C: Hypothalamus. D: Liver. E: Muscle.

FIG. 6.

FIG. 6.

Analysis of pTyr-IRS1 and pTyr-IRS2 signaling and IRS1 expression levels. A_–_H: pTyr-IRS1 (A_–_D) and pTyr-IRS2 (E_–_H) values of insulin-injected fasted mice are displayed relative to those of saline-injected mice. WT lean, WT DIO, and PITIRKO-DIO mice were compared with regard to reproductive and energy storage tissues. n = 4–8/group. A and E: Pituitary. B and F: Ovary. C and G: Liver. D and H: Muscle. I: irs1 mRNA level was measured in pituitary and ovary by real-time PCR in fed mice. J: IRS1 protein level shown by Western blot. K: IRS1 basal protein level was measured by Luminex assay in fed mice. Bars with different letters are significantly different (P < 0.05). (A high-quality color representation of this figure is available in the online issue.)

FIG. 7.

FIG. 7.

HFD-induced inflammation in different tissues. A: Macrophage infiltration was detected by immunohistochemistry using antibody F4/80. B: pJNK was examined by Western blot in different tissues. (A high-quality digital representation of this figure is available in the online issue.)

FIG. 8.

FIG. 8.

A model summarizing the insulin-signaling pathways in the liver, muscle, and pituitary of lean or DIO mice. Arrows indicate active signaling pathways, and an X over the arrow indicates blocked signaling pathways. PI3K, PI 3-kinase.

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