Pirt deficiency has subtle female-specific effects on energy and glucose metabolism in mice

Mol Metab. 2019 May:23:75-81. doi: 10.1016/j.molmet.2019.02.011. Epub 2019 Mar 7.


Objective: The contribution of brown adipose tissue (BAT) to adult human metabolic control is a topic of ongoing investigation. In context, understanding the cellular events leading to BAT uncoupling, heat production, and energy expenditure is anticipated to produce significant insight into this endeavor. The phosphoinositide interacting regulator of transient receptor potentials (Pirt) was recently put forward as a key protein regulating cold sensing downstream of the transient receptor potential melastatin 8 (TRPM8). Notably, TRPM8 has been identified as a non-canonical regulator of BAT thermogenesis. The aim of this investigation was to delineate the role of Pirt in energy homeostasis and glucose metabolism - and the possible involvement of Pirt in TRPM8-elicited energy expenditure.

Methods: To this end, we metabolically phenotyped male and female Pirt deficient (Pirt-/-) mice exposed to a low-fat chow diet or to a high-fat, high-sugar (HFHS) diet.

Results: We identified that chow-fed female Pirt-/- mice have an increased susceptibility to develop obesity and glucose intolerance. This effect is abrogated when the mice are exposed to a HFHS diet. Conversely, Pirt-/- male mice display no metabolic phenotype on either diet relative to wild-type (WT) control mice. Finally, we observed that Pirt is dispensable for TRPM8-evoked energy expenditure.

Conclusion: We here report subtle metabolic abnormalities in female, but not male, Pirt-/- mice. Future studies are required to tease out if metabolic stressors beyond dietary interventions, e.g. temperature fluctuations, are interacting with Pirt-signaling and metabolic control in a sex-specific fashion.

Keywords: Body weight; Brown adipose tissue; Energy metabolism; Sex differences; Signaling molecule; TRPM8.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Animals
  • Calcium Channel Agonists / pharmacology
  • Carrier Proteins / genetics*
  • Diet, Fat-Restricted
  • Diet, High-Fat
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Female
  • Gene Knockout Techniques
  • Glucose / metabolism*
  • Glucose Intolerance / metabolism
  • Glucose Tolerance Test
  • Male
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism
  • Pyrimidinones / pharmacology
  • Sex Factors
  • TRPM Cation Channels / agonists
  • TRPM Cation Channels / metabolism
  • Thermogenesis / drug effects
  • Transcriptome


  • Calcium Channel Agonists
  • Carrier Proteins
  • Membrane Proteins
  • Pirt protein, mouse
  • Pyrimidinones
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • icilin
  • Glucose