The regulators of the central control of sympathetic tone to brown fat are not well understood, particularly those which activate BAT thermogenesis after a meal. In order to better define these pathways we used a range of chemogenetic approaches where Cre-dependent excitatory (hM3Dq) or inhibitory (hM4Di) DREADDs were either injected into (i) the mediobasal hypothalamus (arcuate nucleus, ARC) of POMC-ires-Cre mice or (ii) into the same region of wild type mice that have received a prior injection of a retrogradely-transported AAV-Cre into the T2 –T4 segments of the spinal cord. The former targeting ARC POMC neurons globally and the latter those ARC neurons projecting to sympathetic outflows in the spinal cord. The excitatory and inhibitory DREADDs were subsequently activated with CNO while measuring interscapular BAT activity (temperature of the tissue) using indwelling thermistors.
Activation of excitatory DREADD receptors in all POMC neurons increased BAT temperature above that of control injected (p<0.0001), an effect completely abolished by intracerebroventricular pre-treatment with the MC3/4R antagonist, SHU9119. While inhibition (hM4Di) of POMC neurons had no effect on BAT temperature alone, it did significantly attenuate the postprandial thermogenic response in fast-refed mice (p=0.002). Using the dual viral approach, hM3Dq-mediated activation of POMC neurons that project specifically to the spinal cord recapitulated the increase in BAT temperature seen with activation of all POMC neurons.
Our data confirm that POMC neurons are key regulators of BAT thermogenesis and are consistent with the notion that targeting specifically those neurons projecting to sympathetic outflows in the spinal cord may represent a strategy for increasing energy expenditure.