Loss of ovarian function in association with a high-fat diet promotes insulin resistance and disturbs adipose tissue immune homeostasis

Authors: PAE, MUNKYONG - Chungbuk National University; BAEK, YUNJUNG - Chungbuk National University; LEE, SEUNG-EUN - National Institute Of Horticultural & Herbal Science (NIHHS); WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/8/2018
Publication Date: 4/6/2018
Citation: Pae, M., Baek, Y., Lee, S., Wu, D. 2018. Loss of ovarian function in association with a high-fat diet promotes insulin resistance and disturbs adipose tissue immune homeostasis. Journal of Nutritional Biochemistry. 57:93-102. https://doi.org/10.1016/j.jnutbio.2018.03.0110955-2863.
DOI: https://doi.org/10.1016/j.jnutbio.2018.03.0110955-2863

Interpretive Summary: The loss of ovary function, which occurs in menopause or after removal of ovaries, is associated with a complex physical disorder known as insulin resistance. Insulin resistance impairs the ability of blood sugar to be taken up into the body's cells and used for energy. Menopause and high fat diets are known to increase the risk of developing insulin resistance, respectively. However, it is not clear how menopause combined with a high fat diet is able to affect insulin resistance as well as the body's immune system response. Using both mice with ovaries removed surgically and mice with intact, functioning ovaries, we found that a high-fat diet worsened insulin resistance in mice without ovaries compared to mice with intact, functioning ovaries. Also, we found that a high-fat diet increased the presence of immune cells that cause inflammation in fat tissue in mice after surgical removal of ovaries, and these changes correlated with increased insulin resistance. This study has provided the first evidence indicating that a high fat diet coupled with loss of ovary function can interact to worsen impaired immune function as well as insulin resistance. These findings suggest that consuming a low fat diet and maintaining a normal weight might be a useful approach for women to prevent inflammatory and other physical disorders after menopause. Overall, the clinical implications of these findings may help in developing dietary guidance for menopausal women.

Technical Abstract: Loss of ovarian function, as occurs in menopause or after ovariectomy (OVX), is associated with insulin resistance. Tissue inflammation is suggested to be a key component of obesity-induced insulin resistance in male rodents, with a variety of immune cell types accumulating in adipose tissue. However, the mechanism by which loss of ovarian function promotes insulin resistance remains unclear. Here, we tested the interaction between diets and OVX on metabolic and immune parameters to see whether a high-fat (HF) diet aggravates ovariectomy-associated adipose tissue inflammation and insulin resistance. Nine-week-old Sham and OVX-treated C57Bl/6 mice were fed low-fat (LF) diet or HF diet (60 percent) up to 16 weeks. Glucose metabolism was assessed and adipose tissue and spleen were characterized for tissue inflammation and immune cell populations. HF diet induced glucose intolerance in both OVX mice and, to a lesser extent, Sham mice. With LF diet, OVX mice were significantly protected from glucose intolerance, comparable to Sham mice. Additionally, OVX mice only when exposed to HF diet displayed alterations in adipose tissue inflammation, along with increased accumulation of adipose tissue macrophages, preferentially toward M1-like phenotype, increased numbers of T cells, B cells, and NK cells, compared to those with intact ovarian function. Interestingly, HF diet induced expansion of regulatory T cells in gonadal adipose tissue of both Sham and OVX mice. There were strong positive correlations between insulin resistance index HOMA-IR and the number of immune cells: CD11c plus ATM (r=0.724, p<0.001), CD3 T cells (r=0.729, p<0.001), B cells (r=0.773, p<0.001), and NK cells (r=0.589, p<0.001). Our findings indicate that ovarian function may play a role in determining the response to HF diet-induced obesity as well as the resulting insulin resistance and adipose tissue inflammation by altering adipose tissue immune homeostasis.