Effects of high fat diet on metabolic health vary by age of menopause onset

Abstract

Menopause accelerates metabolic dysfunction, including (pre-)diabetes, obesity and visceral adiposity. However, the effects of endocrine vs. chronological aging in this progression are poorly understood. We hypothesized that menopause, especially in the context of middle-age, would exacerbate the metabolic effects of a high fat diet. Using young-adult and middle-aged C57BL/6J female mice, we modeled diet-induced obesity via chronic administration of high fat (HF) diet vs. control diet. We modeled peri-menopause/menopause via injections of 4-vinylcyclohexene diepoxide, which accelerates ovarian failure vs. vehicle. We performed glucose tolerance tests 2.5 and 7 months after diet onset, during the peri-menopausal and menopausal phases, respectively. Peri-menopause increased the severity of glucose intolerance and weight gain in middle-aged, HF-fed mice. Menopause increased weight gain in all mice regardless of age and diet, while chronological aging drove changes in adipose tissue distribution towards more visceral vs. subcutaneous adiposity. These data are in line with clinical data showing that post-menopausal women are more susceptible to metabolic dysfunction and suggest that greater chronological age exacerbates the effects of endocrine aging (menopause). This work highlights the importance of considering both chronological and endocrine aging in studies of metabolic health.

Figure 1.

Metabolic effects of peri-menopause vary by age of onset. (A) Experimental Timeline. (B) Blood glucose levels 2.5 months after the onset of the dietary intervention, for young adult onset (left panel) and middle-aged onset (middle panel) mice. n=9-15/group, repeated measures ANOVA for each age group. (Right panel) AUC measured 2.5 months after diet onset, during “peri-menopausal” period. 3-way ANOVA with Sidak’s multiple comparisons (C) % Change in body weight after 3 months on the HF or Control diet. 3-way ANOVA with Sidak’s multiple comparisons. n=9-15/group, *p<0.05, **p<0.01, ****p<0.0001. Main effects are written above graphs and post-hoc differences appear on graphs. HF = high fat; Ctrl = control; Pre-meno = pre-menopausal; Peri-meno = peri-menopausal; Meno = menopausal

Figure 2.

Metabolic effects of menopause vary by age of onset. (A) AUC from the GTT performed 7 months after diet onset, during “menopausal” period. (B) Visceral adipose tissue (VAT) wet weights were dissected at the end of the study. (C) Adipose tissue distribution at the end of the study measured as the ratio of visceral vs subcutaneous fat wet weights. n=8-15/group, 3-way ANOVA with Sidak’s post-hoc differences *p<0.05, **p<0.01, ****p<0.0001. Main effects are written above graphs and post-hoc differences appear on graphs. HF = high fat; Ctrl = control; Pre-meno = pre-menopausal; Meno = menopausal; VAT = visceral adipose tissue; SAT = subcutaneous adipose tissue