The evolutionary necessity of an organism to adapt to cycles of food scarcity has led to the development of intricate counter regulatory mechanisms central to the maintenance of energy homeostasis. The brain represents a critical nexus in the regulation of energy balance however the functional neuronal circuitry orchestrating the adaption of metabolism processes remains undefined.
Utilising activity dependent labelling of cell populations to gain selective genetic access to neurons activated by energy deprivation, we have defined a novel neuroendocrine neuronal ensemble in the mediobasal hypothalamus (MBH) central to the orchestration of metabolic adaption. We demonstrate that this neuronal ensemble can regulate inter and multi organ metabolic reprogramming to profoundly influence whole body metabolism. This diverse neuronal ensemble is comprised of a heterogeneous population of both canonical metabolically relevant neurons and non-canonical neurons. Selective ensemble-specific chemogenetic for only 5-days leads to a profound and rapid increase in body weight and adiposity via enhanced caloric intake, a shift towards systemic carbohydrate utilisation, attenuated energy expenditure, and promotion of glycolysis and glucose utilisation in glycolytic muscles.
The peripheral metabolic cue governing the activation state of this MBH neuronal ensemble is undefined. Combining TRAP technology and CRIPSR-Cas9 gene editing we generated a mouse model lacking functional insulin receptors exclusively within this MBH neuronal ensemble. This resulted in a profound gain in body weight, adiposity, food intake and suppressed energy expenditure. This demonstrates postprandial pancreatic insulin secretion as the predominant hormonal cue that signal and tunes the MBH metabolic circuitry to the perceived metabolic demands of the body.
We demonstrate a previously undefined neuroendocrine ensemble paramount to the initiation of integrative mechanisms that adapt metabolism under different needs states. These findings set the precedent for neuronal ensembles as critical initiators of an intricate repertoire of physiological, behavioural, and biochemical processes central to metabolic homeostasis.