Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control

• LH regulates respiration via ORX cells.
• LH regulates energy balance via ORX, MCH and LepR cells.
• ORX, MHC, and LepR cells sense and integrate key feedback signals.

Physiological fluctuations in the levels of hormones, nutrients, and gasses are sensed in parallel by interacting control systems distributed throughout the brain and body. We discuss the logic of this arrangement and the definitions of “sensing”; and then focus on lateral hypothalamic (LH) control of energy balance and respiration. LH neurons control diverse behavioral and autonomic processes by projecting throughout the neuraxis. Three recently characterized types of LH cells are discussed here. LH orexin/hypocretin (ORX) neurons fire predominantly during wakefulness and are thought to promote reward-seeking, arousal, obesity resistance, and adaptive thermogenesis. Bidirectional control of ORX cells by extracellular macronutrients may add a new regulatory loop to these processes. ORX neurons also stimulate breathing and are activated by acid/CO2in vivo and in vitro. LH melanin-concentrating hormone (MCH) neurons fire mostly during sleep, promote physical inactivity, weight gain, and may impair glucose tolerance. Reported stimulation of MCH neurons by glucose may thus modulate energy homeostasis. Leptin receptor (LepR) neurons of the LH are distinct from ORX and MCH neurons, and may suppress feeding and locomotion by signaling to the mesolimbic dopamine system and local ORX neurons. Integration within the ORX–MCH–LepR microcircuit is suggested by anatomical and behavioral data, but requires clarification with direct assays of functional connectivity. Further studies of how LH circuits counteract evolutionarily-relevant environmental fluctuations will provide key information about the logic and fragilities of brain controllers of healthy homeostasis.