Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity

Brown adipose tissue(BAT)is an energy-expending organ that produces heat.Expansion or activation of BAT prevents obesity and diabetes.Chronic cold exposure enhances thermogenesis in BAT through uncoupling protein 1(UCP1)activation triggered via a b-adrenergic pathway.Here,we report that the cold-sensing transient receptor potential melastatin 8(TRPM8)is functionally present in mouse BAT.Challenging brown adipocytes with menthol,a TRPM8 agonist,up-regulates UCP1 expression and requires protein kinase A activation.Upon mimicking long-term cold exposure with chronic dietary menthol application,menthol significantly increased the core temperatures and locomotor activity in wild-type mice;these effects were absent in both TRPM82/2 and UCP12/2 mice.Dietary obesity and glucose abnormalities were also prevented by menthol treatment.Our results reveal a previously unrecognized role for TRPM8,suggesting that stimulation of this channel mediates BAT thermogenesis,which could constitute a promising way to treat obesity.

Chronic hypoperfusion due to intracranial large artery stenosis is not associated with cerebralβ-amyloid deposition and brain atrophy

Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology.We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.Methods:We enrolled a group of cognitively normal patients(median age:64 years)with unilateral chronic cerebral hypoperfusion.Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion.11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.Results:The median age of the 10 participants,consisting of 4 males and 6 females,was 64 years(47-76 years).We found that there were no differences in standard uptake ratios of the cortex(volume of interest[VOI]:P=0.721,region of interest[ROI]:P=0.241)and grey/white ratio(VOI:P=0.333,ROI:P=0.445)and brain atrophy indices(Bicaudate,Bifrontal,Evans,Cella,Cella media,and Ventricular index,P>0.05)between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.Conclusion:Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebralβ-amyloid deposition and neurodegeneration in humans.