Aldosterone deficiency prevents high-fat-feeding-induced hyperglycaemia and adipocyte dysfunction in mice

Abstract

Aims/hypothesis Obesity is associated with aldosterone excess, hypertension and the metabolic syndrome, but the relative contribution of aldosterone to obesity-related complications is debated. We previously demonstrated that aldosterone impairs insulin secretion, and that genetic aldosterone deficiency increases glucose-stimulated insulin secretion in vivo. We hypothesised that elimination of endogenous aldosterone would prevent obesity-induced insulin resistance and hyperglycaemia. Methods Wild-type and aldosterone synthase-deficient (As−/−) mice were fed a high-fat (HF) or normal chow diet for 12 weeks. We assessed insulin sensitivity and insulin secretion using clamp methodology and circulating plasma adipokines, and examined adipose tissue via histology. Results HF diet induced weight gain similarly in the two groups, but As−/− mice were protected from blood glucose elevation. HF diet impaired insulin sensitivity similarly in As−/− and wild-type mice, assessed by hyperinsulinaemic–euglycaemic clamps. Fasting and glucose-stimulated insulin were higher in HF-fed As−/− mice than in wild-type controls. Although there was no difference in insulin sensitivity during HF feeding in As−/− mice compared with wild-type controls, fat mass, adipocyte size and adiponectin increased, while adipose macrophage infiltration decreased. HF feeding significantly increased hepatic steatosis and triacylglycerol content in wild-type mice, which was attenuated in aldosterone-deficient mice. Conclusions/interpretation These studies demonstrate that obesity induces insulin resistance independently of aldosterone and adipose tissue inflammation, and suggest a novel role for aldosterone in promoting obesity-induced beta cell dysfunction, hepatic steatosis and adipose tissue inflammation.

Effects of aldosterone on insulin sensitivity and secretion

“…In high fat-, fructose-fed, and genetic models of obesity, MR antagonism ameliorates fatty liver disease with reduction in histologic injury and hepatic triglyceride content (98–100). we similarly observed that aldosterone synthase deficiency ameliorates high fat diet-induced fatty liver histology and hepatic triglyceride content (90). On the other hand, one study found no effect of adrenalectomy or MR antagonism on fatty liver severity (101).…”

“…Some studies argue against a direct adipose tissue affect, however, because aldosterone only impaired insulin signaling at concentrations which activate the glucocorticoid receptor (89). In the setting of diet-induced obesity, genetic aldosterone deficiency reduced adipocyte inflammation and increased circulating adiponectin, although this did not prevent development of obesity or insulin resistance, suggesting that mineralocorticoids other than aldosterone may contribute to insulin resistance in vivo (90). …”

The mineralocorticoid receptor: a new player controlling energy homeostasis

“…These surprising findings suggested that aldosterone modulates insulin secretion via ROS production, but yet independently of MR [53]. More recently, the same group demonstrated that AS KO mice were relatively protected against HFD-induced beta cell dysfunction, hepatic steatosis, suggesting that aldosterone could be involved in the development of these obesity-associated diseases [54]. Thus, aldosterone could alter insulin secretion through hypokaliemia, induction of islet inflammation or oxidative stress.…”

Adipocytes, aldosterone and obesity-related hypertension

“…However, weight gain was unchanged and fasting insulin was highest in the aldosterone synthase knockout mice on the high-fat diet (Luo et al 2013). This suggests involvement of aldosterone in some but not all of the adipose tissue dysfunction related to insulin resistance associated with obesity.…”