Diabetes prevalence in NZO females depends on estrogen action on liver fat content

Abstract

In humans and rodents, risk of metabolic syndrome is sexually dimorphic, with an increased incidence in males. Additionally, the protective role of female gonadal hormones is ostensible, as prevalence of type 2 diabetes mellitus (T2DM) increases after menopause. Here, we investigated the influence of estrogen (E2) on the onset of T2DM in female New Zealand obese (NZO) mice. Diabetes prevalence (defined as blood glucose levels >16.6 mmol/l) of NZO females on high-fat diet (60 kcal% fat) in week 22 was 43%. This was markedly dependent on liver fat content in week 10, as detected by computed tomography. Only mice with a liver fat content >9% in week 10 plus glucose levels >10 mmol/l in week 9 developed hyperglycemia by week 22. In addition, at 11 wk, diacylglycerols were elevated in livers of diabetes-prone mice compared with controls. Hepatic expression profiles obtained from diabetes-prone and -resistant mice at 11 wk revealed increased abundance of two transcripts in diabetes-prone mice: Mogat1, which catalyzes the synthesis of diacylglycerols from monoacylglycerol and fatty acyl-CoA, and the fatty acid transporter Cd36. E2 treatment of diabetes-prone mice for 10 wk prevented any further increase in liver fat content and reduced diacylglycerols and the abundance of Mogat1 and Cd36, leading to a reduction of diabetes prevalence and an improved glucose tolerance compared with untreated mice. Our data indicate that early elevation of hepatic Cd36 and Mogat1 associates with increased production and accumulation of triglycerides and diacylglycerols, presumably resulting in reduced hepatic insulin sensitivity and leading to later onset of T2DM.

Acylcarnitine Profiles in Plasma and Tissues of Hyperglycemic NZO Mice Correlate with Metabolite Changes of Human Diabetes

“…In our study, female mice remained normoglycemic, which is in line with previous literature stating protective effects of oestrogen [ 1 , 6 ]. We furthermore observed a large variation in the development and severity of hyperglycemia within the male group since numbers for age and fasted blood glucose concentrations at the onset of T2DM vary among the studies and make it difficult to define the beginning of diabetic perturbations by distinct biomarkers [ 2 , 17 , 18 ].…”

Animal models of obesity and diabetes mellitus

“…Similar to what occurs in humans, the onset of T2DM in NZO mice decidedly depends on the degree of hepatosteatosis early in life. When the liver fat content is <10% at the age of 10 weeks, NZO mice are protected from ensuing hyperglycaemia and β-cell loss 244 . Dietary interventions such as a moderate calorie restriction or intermittent fasting (fasting every other day) can protect NZO mice from hyperglycaemia.…”

Metabolic changes during pregnancy in glucose‐intolerant NZO mice: A polygenic model with prediabetic metabolism

“…However, female mice of this strain are protected from hyperglycemia and β‐cell death due to the sex hormone estrogen. But glycemic control of female NZO impairs following long‐term administration of high‐fat diet or after ovarectomy and animals develop a disease pattern of T2DM similar to that of humans (Lubura et al, 2015; Vogel et al, 2013).…”