Hypothalamic nutrient sensing in the control of energy homeostasis

The hypothalamus is a center of convergence and integration of multiple nutrient-related signals. It can sense changes in circulating adiposity hormones, gastric hormones and nutrients, and receives neuroanatomical projections from other nutrient sensors, mainly within the brainstem. The hypothalamus also integrates these signals with various cognitive forebrain-descending information and reward/motivation-related signals coming from the midbrain-dopamine system, to coordinate neuroendocrine, behavioral and metabolic effectors of energy balance. Some of the key nutrient-sensing hypothalamic neurons have been identified in the arcuate, the ventro-medial and the lateral nuclei of the hypothalamus, and the molecular mechanisms underlying intracellular integration of nutrient-related signals in these neurons are currently under intensive investigation. However, little is known about the neural pathways downstream from hypothalamic nutrient sensors, and how they drive effectors of energy homeostasis under physiological conditions. This manuscript will review recent progress from molecular, genetic and neurophysiological studies that identify and characterize the critical intracellular signalling pathways and neurocircuits involved in determining hypothalamic nutrient detection, and link these circuits to behavioral and metabolic effectors of energy balance. We will provide a critical analysis of current data to identify ongoing challenges for future research in this field.