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

Abstract

The anorectic mouse exhibits a mitochondrial complex I dysfunction that is related to aberrant expression of hypothalamic neuropeptides and transmitters regulating food intake. Hypothalamic activity, i.e. neuronal firing and transmitter release, is dependent on glucose utilization and energy metabolism. To better understand the role of hypothalamic activity in anorexia, we assessed carbohydrate and high-energy phosphate metabolism, and , in the hypothalamus. In the fasted state, hypothalamic glucose uptake in the mouse was reduced by ~50% of that seen in wild-type (wt) mice ( < 0.05). Under basal conditions, hypothalamus ATP and glucose 6-P contents were similar to those in wt hypothalamus, whereas phosphocreatine was elevated (~2-fold; < 0.001) and lactate was reduced (~35%; < 0.001). The hypothalamus had elevated total AMPK (~25%; < 0.05) and GLUT4 (~60%; < 0.01) protein contents, whereas GLUT1 and GLUT3 were similar to that of wt hypothalamus. Interestingly, the activation state of AMPK (ratio of phosphorylated AMPK/total AMPK) was significantly decreased in hypothalamus of the mouse (~60% of that in wt; < 0.05). Finally, during metabolic stress (ischemia), accumulation of lactate (measure of glycolysis) and IMP and AMP (breakdown products of ATP) were ~50% lower in vs wt hypothalamus. These data demonstrate that carbohydrate and high-energy phosphate utilization in the hypothalamus are diminished under basal and stress conditions. The decrease in hypothalamic metabolism may contribute to the anorectic behavior of the mouse, i.e. its inability to regulate food intake in accordance with energy status.

The anx/anx Mouse – A Valuable Resource in Anorexia Nervosa Research

“…In some cases, conversely, mitochondrial dysfunction is associated with reduced glucose uptake and hypometabolism, e.g., in Alzheimer’s disease and epilepsy (Chandrasekaran et al, 1996; Tenney et al, 2014). This resembles what we saw in the anx/anx hypothalamus, i.e., lower glucose uptake rate, decreased lactate content, as well as elevated phosphocreatine (PCr) content and reduced activation of AMP-activated kinase (AMPK) in the basal state (Bergstrom et al, 2017). This is similar to the hypometabolic state seen in hibernation (Healy et al, 2011) and could be reflecting lower neuronal activity (Cunnane et al, 2011).…”

Hypothalamic and brain stem neurochemical profile in anorectic rats after peripheral administration of kisspeptin‐10 using 1H‐nmr spectroscopy in vivo

“…The most relevant for energy balance are changes in creatine and phosphocreatine as related to ATP production. Observed phosphocreatine elevation is consistent with reports about reduced hypothalamic metabolism in anorectic mice 47 . On the other hand, brain glucose levels seem to be reduced which could indicate its increased utilization, and hypoglycemia is a common finding in AN patients and their response to compensatory ghrelin stimulation of glycaemia is impaired.…”

The Utility of Animal Models for Studying the Metabo-Psychiatric Origins of Anorexia Nervosa

“…Notably, the spontaneous anx mutation identified in mice induces abnormalities within the hypothalamus, involving an aberrant AgRP/NPY system (64,72). Additionally, anx/anx mice display decreases in hypothalamic activity accompanied by impaired glucose utilization and energy metabolism (73). However, it remains unknown which gene is responsible for the phenotype of anx/anx mice, or whether AN patients show variation within the responsible gene.…”