14-3-3ζ over-expression improves tolerance to acute and chronic cold exposure in male mice via thermogenic-dependent and -independent mechanisms

Adaptive thermogenesis, which is partly mediated by sympathetic input on brown adipose tissue (BAT), is a mechanism of heat production in response to prolonged cold that relies upon the actions of Uncoupling Protein-1 (UCP1). Moreover, various stimuli, including norepinephrine and FGF-21, promote the conversion of inguinal white adipocytes to beige adipocytes, which represent a secondary cell type that can contribute to adaptive thermogenesis. Although we previously identified an essential role of the molecular scaffold 14-3-3ζ in adipogenesis, one of the earliest, identified functions of 14-3-3ζ is its regulatory effects on the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of norepinephrine. This suggests that 14-3-3ζ could influence adaptive thermogenesis via actions on BAT activation or the beiging of white adipocytes. Herein, we report that transgenic over-expression of 14-3-3ζ (TAP) in male mice significantly improved tolerance to acute (3 hrs) and chronic (3 days) cold (4 °C) exposure. In response to cold,increased UCP1 expression in beige inguinal white tissue (iWAT) and BAT was observed in TAP mice following chronic cold exposure, in addition to significantly elevated body temperature. Of note was the paradoxical finding that cold-induced increases in body temperature were associated with significantly decreased energy expenditure in TAP mice. The marked improvements in cold tolerance were not due to changes in sensitivity to β-adrenergic stimulation; instead over-expression of 14-3-3ζ significantly decreased thermal conductance and heat loss in mice via increased peripheral vasoconstriction. Despite displaying elevations in cold-induced UCP1 expression in brown or beige adipocytes, these findings suggest alternative mechanisms that can be activated to mitigate heat loss during chronic cold exposure. Collectively, our results point to novel roles of 14-3-3ζ in regulating non-thermogenic mechanisms that regulate body temperature.