Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

TRPM8 is a potential therapeutic target for obesity and diabetes. (#108)

Xiangjun Jin 1 , Michael Cowley 1 , Stephanie Simonds 1
  1. Monash University, Clayton, VIC, Australia

Increasing energy expenditure by increasing brown adipose tissue (BAT) thermogenesis or promoting white adipose tissue (WAT) browning is a promising therapeutic strategy to combat obesity [1]. The cold-sensing and menthol-activated ion-channel transient-receptor-potential-melastatin-8 (TRPM8) has been shown to regulate energy homeostasis. TRPM8 is primarily expressed in the peripheral nervous system (PNS) [2, 3]. Ex vivo and in vitro studies suggested that activation of TRPM8 increases energy expenditure and BAT thermogenesis [3-5]. We aim to investigate the cell type expressing TRPM8 in PNS, and the role of TRPM8 in regulating energy and glucose metabolism in mice. 

To determine the expression of TRPM8 in PNS, dorsal root ganglions (DRGs) were collected from male and female mice aged 40 to 60 days. TRPM8 expression was assessed in the TRPM-hrGFP-Cre mice, with C57BL/6 (WT), vesicular-glutamate-transport-2 (VGLUT2)-Cre mice used as controls. Immunohistochemistry was performed using anti-Cre staining. Compared to the DRGs from WT mice, Cre expression was observed in DRGs from TRPM8-hrGFP-Cre and VGLUT2-Cre mice. TRPM8 was mainly expressed in small-sized neurons within the DRGs compared to VGLUT2, with further colocalization characterisation of the TRPM8-expressing neurons ongoing.

To determine the role of TRPM8 in metabolism, WT mice were treated with TRPM8 agonist or vehicle for 14 consecutive days. BAT was collected with UCP-1 immunohistochemistry conducted. Compared to vehicle-treated WT mice, increased expression of UCP-1 was observed in BAT from mice post TRPM8 agonist treatment. Additionally, TRPM8 agonist reduced plasma blood glucose concentration whilst elevating BAT temperature and increasing energy expenditure, measured in a TSE equipment at 23˚C and thermoneutrality.

These findings suggested that TRPM8 is expressed in the small neurons in the DRG. Activation of TRPM8 reduced blood glucose levels and increased energy expenditure. Future studies will involve double-staining to identify the cell types of TRPM8-positive neurons in the DRG. We expect that activation of TRPM8 in DRGs will increase energy expenditure and reduce blood glucose levels.

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  3. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416(6876):52-8.
  4. Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y, et al. Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. Journal of Molecular Cell Biology. 2012;4(2):88-96.
  5. Khare P, Chauhan A, Kumar V, Kaur J, Mahajan N, Kumar V, et al. Bioavailable Menthol (Transient Receptor Potential Melastatin-8 Agonist) Induces Energy Expending Phenotype in Differentiating Adipocytes. Cells. 2019;8(5).