Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK

Abstract

Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16 days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by 9 folds in TD group. The loss of body weight (17–24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic AMPK is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight.

Associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of Wernicke's encephalopathy

“…C57Bl/6 mice fed a thiamine deficient diet for 16 days showed severe (17–24%) weight loss related to significant decreases in food intake and increases in resting energy expenditure; experiments suggested that thiamine deficiency may inhibit a critical regulator of food intake, hypothalamic adenosine monophosphate-activated protein kinase (AMPK) (Liu et al, 2014). Thiamine deficiency also resulted in changes to physiology and behavior including piloerection, splayed legs, gait problems, loss of trunk tone, and loss of righting reflex.…”

Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy

“…It has now been established that TD is the primary cause of WKS. Clinically, WKS is usually associated with chronic alcoholism which depletes thiamine in the human body, but it can also be caused by malnourishment [43, 44]. …”

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

“…This mechanism is common to several orexigenic signals, such as hypoglycaemia, ghrelin, glucocorticoids, adiponectin, and cannabinoids [117,[119][120][121][122][123][124][125] . Some anorexigenic signals, such as leptin, insulin, GLP-1, ciliary neurotrophic factor, thiamine deficiency, and melanocortin receptor agonists, also exert their effects inhibiting hypothalamic AMPK [117,118,120,[126][127][128][129][130][131][132] ( Fig. 1 ).…”

“…Interestingly, leptin action is also mediated by the AMPK inhibition that occurs in the ARC, VMH, and PVH, where, as a result of that action, the concentration of palmitoyl-CoA is increased [118,128,133] . In this regard, the role of AMPK in the PVH has been investigated thoroughly, demonstrating that, besides leptin, AMPK is modulated in similarity to other nuclei by hypoglycaemia and thiamine [132,134] but not by ciliary neurotrophic factor [127] , demonstrating anatomical specificity. Finally, it has also been proposed that AMPK in vasopressin neurons of the PVH may be involved in adiponectin effects on osmoregulation [135] .…”