Pyruvate induces torpor in obese mice

Abstract

Mice subjected to cold or caloric deprivation can reduce body temperature and metabolic rate and enter a state of torpor. Here we show that administration of pyruvate, an energy-rich metabolic intermediate, can induce torpor in mice with diet-induced or genetic obesity. This is associated with marked hypothermia, decreased activity, and decreased metabolic rate. The drop in body temperature correlates with the degree of obesity and is blunted by housing mice at thermoneutrality. Induction of torpor by pyruvate in obese mice relies on adenosine signaling and is accompanied by changes in brain levels of hexose bisphosphate and GABA as detected by mass spectroscopy-based imaging. Pyruvate does not induce torpor in lean mice but results in the activation of brown adipose tissue (BAT) with an increase in the level of uncoupling protein-1 (UCP1). Denervation of BAT in lean mice blocks this increase in UCP1 and allows the pyruvate-induced torpor phenotype. Thus, pyruvate administration induces torpor in obese mice by pathways involving adenosine and GABA signaling and a failure of normal activation of BAT.

Sex-specific hippocampal metabolic signatures at the onset of systemic inflammation with lipopolysaccharide in the APPswe/PS1dE9 mouse model of Alzheimer’s disease

“…Here, hypothermia was sex-dependent and this was also associated with a reduction in hippocampal pyruvate metabolism particularly affecting APP/PS1 males. A possible link cannot be ruled out as hypothermia was found to cause a progressive decrease in cerebral pyruvate contents in the rat (Nilsson et al, 1975), although central administration of pyruvate did not significantly alter body temperature (Soto et al, 2018). Pyruvate is an intermediate energy metabolite of glucose with potent anti-oxidant and anti-inflammatory actions (Das, 2006).…”

Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle

“…Because it has been shown that gluconeogenesis is activated in liver of fasted obese human, ob / ob mice, and high-fat diet-fed mice ( Turner et al., 2005 ; Basu et al., 2005 ; Satapati et al., 2012 ), gluconeogenesis is likely to be relatively more dominant than glycolysis in liver of fasted ob / ob mice. Besides, it has been reported to increase the blood glucose level in fasted db / db mice, a leptin receptor-deficient mice ( Clementi et al., 2011 ; Liu et al., 2012 ), and high-fat diet-fed mice more than in wild-type mice and standard-chow-diet-fed mice ( Soto et al., 2018 ), respectively, by intraperitoneal pyruvate administration. These results also support our interpretation that gluconeogenesis is more dominant than glycolysis.…”

Brown and Brite: The Fat Soldiers in the Anti-obesity Fight

“…Small molecule circulating regulators of BAT physiology include hydrogen sulfide (H 2 S) (Soriano et al, 2018), pyruvate (Soto et al, 2018) and abscisic acid (Sturla et al, 2017).…”