KATP-Channel-Dependent Regulation of Catecholaminergic Neurons Controls BAT Sympathetic Nerve Activity and Energy Homeostasis

• Expression of a variant KATP channel in TH cells enhances obesity
• KATP-channel-dependent neuronal excitability in TH cells controls BAT SNA
• TH-positive neurons in the LC are glucose responsive
• KATP-dependent control of LC neurons regulates BAT SNA and energy homeostasis

SummaryBrown adipose tissue (BAT) is a critical regulator of glucose, lipid, and energy homeostasis, and its activity is tightly controlled by the sympathetic nervous system. However, the mechanisms underlying CNS-dependent control of BAT sympathetic nerve activity (SNA) are only partly understood. Here, we demonstrate that catecholaminergic neurons in the locus coeruleus (LC) adapt their firing frequency to extracellular glucose concentrations in a KATP-channel-dependent manner. Inhibiting KATP-channel-dependent control of neuronal activity via the expression of a variant KATP channel in tyrosine-hydroxylase-expressing neurons and in neurons of the LC enhances diet-induced obesity in mice. Obesity results from decreased energy expenditure, lower steady-state BAT SNA, and an attenuated ability of centrally applied glucose to activate BAT SNA. This impairs the thermogenic transcriptional program of BAT. Collectively, our data reveal a role of KATP-channel-dependent neuronal excitability in catecholaminergic neurons in maintaining thermogenic BAT sympathetic tone and energy homeostasis.