14-3-3ζ mediates an alternative, non-thermogenic mechanism to reduce heat loss and improve cold tolerance

Summary Following prolonged cold exposure, adaptive thermogenic pathways are activated to maintain homeothermy, and elevations in body temperature are generally associated with UCP1-dependent and -independent increases in energy expenditure. One of the earliest, identified functions of the molecular scaffold, 14-3-3ζ, was its role in the synthesis of norepinephrine, a key endogenous factor that stimulates thermogenesis. This suggests that 14-3-3ζ may have critical roles in cold-induced thermogenesis. Herein, we report that transgenic over-expression of TAP-14-3-3ζ in mice significantly improved tolerance to prolonged cold. When compared to wildtype controls, TAP mice displayed significantly elevated body temperatures and paradoxical decreases in energy expenditure. No changes in β-adrenergic sensitivity or oxidative metabolism were observed; instead, 14-3-3ζ over-expression significantly decreased thermal conductance via increased peripheral vasoconstriction. These findings suggest 14-3-3ζ mediates alternative, non-thermogenic mechanisms to mitigate heat loss for homeothermy. Our results point to an unexpected role of 14-3-3ζ in the regulation of body temperature. Graphical abstract