Energy deprivation triggers profound metabolic shifts orchestrated by intricate counterregulatory mechanisms. The hypothalamus emerges as a central node in coordinating the holistic response necessary to adapt metabolism to the body's current requirements. Traditional approaches to studying the hypothalamus have focused on categorising neurons based on peptide/receptor expression, limiting our ability to uncover their functional relationships. Consequently, the functional neuronal circuitry orchestrating metabolic adaptation remains largely uncharted.
To bridge this knowledge gap, we employed Targeted Recombination in Active Populations (TRAP) to functionally pinpoint the neuronal circuit governing metabolic adaptation. Our methodology unveiled a neuroendocrine ensemble situated in the mediobasal hypothalamus, pivotal in regulating whole-body metabolism. Single-cell transcriptomic analysis revealed the ensemble's inherent heterogeneity, encompassing both canonical metabolically relevant neurons and non-canonical neurons. Activation of this ensemble through selective chemogenetic methods resulted in rapid increases in body weight and adiposity, driven by elevated caloric intake, heightened food-seeking behaviour, reduced energy expenditure, and alterations in fuel utilisation. In vivo, metabolic tracing unveiled heightened fatty acid uptake and triglyceride incorporation in the liver, alongside a shift toward carbohydrate oxidation in muscle. Subsequent lipidomic analysis corroborated these tissue-specific nutrient shifts.
Notably, ablating this neuronal circuit using Caspase-3 or Diphtheria Toxin rendered the organism unable to stimulate feeding and suppress energy expenditure during periods of energy deficits, underscoring its essential role in orchestrating whole-body metabolic reprogramming. Additionally, by combining TRAP technology with CRISPR-Cas9 gene editing to selectively target insulin receptors within the ensemble, we identified postprandial pancreatic insulin secretion as a critical hormonal cue governing brain-body metabolic reprogramming. Disruption of insulin signalling to this ensemble induced a hyperactive state in these neurons, resulting in significant increases in body weight, adiposity, food intake, and reduced energy expenditure.
In summary, our findings spotlight a novel neuroendocrine ensemble at the forefront of metabolic adaptation in response to metabolic demands. This study not only sheds light on the critical role of neuronal ensembles but also establishes them as pivotal initiators of a complex array of physiological, behavioural, and biochemical processes central to metabolic homeostasis.