Glucose intolerance and pancreatic β-cell dysfunction in the anorecticanx/anxmouse

Abstract

mation and impaired mitochondrial oxidative phosphorylation are considered key players in the development of several metabolic disorders, including diabetes. We have previously shown inflammation and mitochondrial dysfunction in the hypothalamus of an animal model for anorexia, the anx/anx mouse. Moreover, increased incidence of eating disorders, e.g., anorexia nervosa, has been observed in diabetic individuals. In the present investigation we evaluated whether impaired mitochondrial phosphorylation and inflammation also occur in endocrine pancreas of anorectic mice, and if glucose homeostasis is disturbed. We show that anx/anx mice exhibit marked glucose intolerance associated with reduced insulin release following an intraperitoneal injection of glucose. In contrast, insulin release from isolated anx/anx islets is increased after stimulation with glucose or KCl. In isolated anx/anx islets there is a strong downregulation of the mitochondrial complex I (CI) assembly factor, NADH dehydrogenase (ubiquinone) 1␣ subcomplex, assembly factor 1 (Ndufaf1), and a reduced CI activity. In addition, we show elevated concentrations of free fatty acids (FFAs) in anx/anx serum and increased macrophage infiltration (indicative of inflammation) in anx/anx islets. However, isolated islets from anx/anx mice cultured in the absence of FFAs do not exhibit increased inflammation. We conclude that the phenotype of the endocrine pancreas of the anx/anx mouse is characterized by increased levels of circulating FFAs, as well as inflammation, which can inhibit insulin secretion in vivo. The anx/anx mouse may represent a useful tool for studying molecular mechanisms underlying the association between diabetes and eating disorders.anorexia; free fatty acids; insulin; macrophages; mitochondrial dysfunction THERE IS INCREASING EVIDENCE that inflammation in animals and humans is important for the development of several metabolic disorders, including diabetes (2,8,9,46,47,49). Animal studies show that inflammation induced by obesity following high-fat diet is associated with insulin and leptin resistance, lost control of energy expenditure, macrophage infiltration, and pancreatic islet dysfunction (2, 21, 49).The anorectic anx/anx mouse arose by a spontaneous mutation in 1976. These mice develop self-starvation and emaciation and die at about 3 wk of age (32). They eat approximately half as much as the normal littermates (32). Thus the anx/anx mouse is an attractive model for studying regulation of feeding behavior, in particular anorexia, due to the development of core features associated with human conditions such as anorexia nervosa (AN) (24) and failure to thrive (23). The anx/anx mouse exhibits several alterations in hypothalamic neurotransmitter/peptide circuits involved in regulation of food intake (4 -6, 12, 20, 37, 38). Moreover, the anx mutation is linked to downregulation of the NADH dehydrogenase (ubiquinone) 1␣ subcomplex, assembly factor 1 (Ndufaf1), involved in the assembly of complex I (CI) in the mitochondrial oxidative phosph...

Reduced metabolism in the hypothalamus of the anorectic anx/anx mouse

“…To directly examine this possibility, we assessed the rate of glucose uptake in hypothalamus of conscious anx/anx mice. Blood glucose concentration in the fasted state averaged 5.6 ± 0.6 mM in anx/anx and 7.9 ± 0.6 mM in wt mice (P = 0.04), which agrees with our recent findings for both groups under comparable conditions (Lindfors et al 2015). In the fasted state, serum insulin does not differ significantly between groups (Lindfors et al 2015).…”

“…Blood glucose concentration in the fasted state averaged 5.6 ± 0.6 mM in anx/anx and 7.9 ± 0.6 mM in wt mice (P = 0.04), which agrees with our recent findings for both groups under comparable conditions (Lindfors et al 2015). In the fasted state, serum insulin does not differ significantly between groups (Lindfors et al 2015). Glucose uptake was significantly reduced in the hypothalamus of anx/anx compared to that in wt mice (Fig.…”

Dopamine D2 receptor overexpression in the nucleus accumbens core induces robust weight loss during scheduled fasting selectively in female mice

“…Of interest, AN patients in the ill state exhibit glucose intolerance 49 – 53 and a low or delayed insulin response to glucose loading 52 – 54 , which are associated with a poor refeeding outcome 49 . Further, the anorectic anx/anx mouse model also shows marked glucose intolerance, reduced insulin release after glucose loading, and pancreatic beta cell dysfunction 55 . Weight loss and muscle wasting occurs if blood glucose levels becomes too high and excess glucose is removed from the blood by the kidneys and excreted via the urine 56 .…”

Induced Pluripotent Stem Cells; New Tools for Investigating Molecular Mechanisms in Anorexia Nervosa

“…In humans, variants of AGRP are observed in patients with AN (54), and changes in NPY levels in cerebrospinal fluid are secondary to AN (55). The mice also develop inflammation and degeneration in brain areas near neurons expressing AGRP (56, 57) and have dysfunctional pancreases, resulting in glucose intolerance and high levels of circulating free fatty acids (58)—mirroring findings in people with AN (59). However, one limitation of anx/anx mice is that they die approximately 1 month after birth due to mitochondrial dysfunction and neurodegeneration (47).…”