Homeostatic and Hedonic Components Involved in ORL1 Regulation of Energy Homeostasis

This project investigates the synaptic and hormonal determinants that underlie central control of energy homeostasis, with a specific focus on how homeostatic (nutrient-sensing) and hedonic (palatability-sensing) circuits interact to influence energy intake and expenditure. The lab probes key neuropeptides and neuromodulators — including nociceptin/orphanin FQ (N/OFQ), pituitary adenylyl cyclase-activating polypeptide (PACAP), and endocannabinoids — and examines how sex and the activational effects of gonadal hormones shape signaling within these pathways. Using state-of-the-art optogenetic and chemogenetic approaches applied in strategically chosen transgenic animal models, the lab performs cell type–specific excitation or inhibition of anatomically defined substrates to determine consequent changes in feeding behavior, meal patterns, and energy expenditure.

Central to the group’s work is characterization of N/OFQ (nociceptin) actions across both hypothalamic anorexigenic circuits and mesolimbic reward circuitry. In the arcuate nucleus (ARC), N/OFQ-producing neurons inhibit anorexigenic proopiomelanocortin (POMC) neurons through presynaptic and postsynaptic mechanisms. Optogenetic stimulation of ARC N/OFQ neurons in double transgenic N/OFQ-cre/eGFP POMC mice produces a robust, reversible NOP receptor–mediated outward current in POMC neurons that reverses polarity near the K+ equilibrium potential and is accompanied by increased slope conductance. Within hedonic circuitry, N/OFQ likewise inhibits mesolimbic A10 dopamine neurons in the ventral tegmental area (VTA) that modulate natural and drug-induced reward and addictive behaviors, via similar NOP receptor–mediated mechanisms.

The lab’s feeding-circuitry research emphasizes the VMN-to-ARC anorexigenic pathway: PACAP neurons in the ventromedial nucleus synapse on POMC neurons in the ARC. Chemogenetic activation of PACAP neurons increases cFOS expression and firing rates in these cells, resulting in decreased energy intake and meal size along with increased energy expenditure. By contrasting homeostatic and hedonic pathways, the lab delineates how circuits focused on “need” (hypothalamic nutrient sensing) and “want” (mesolimbic palatability and reward) differentially contribute to dysregulated eating.

A translational theme threads the lab’s work: intermittent, short-term exposure to a Westernized high-fat diet provokes binge-like escalations in intake during discrete exposures, and administration of N/OFQ into the VTA attenuates this binge-like behavior through NOP receptor mechanisms in a way that depends on sex, gonadal hormone milieu, and dietary status. Current hypotheses under investigation include whether chemostimulation or photostimulation of ARC N/OFQ neurons stimulates energy intake and reduces energy expenditure in chow- versus high-fat diet–fed males and females, whether photostimulation hyperpolarizes POMC neurons via GIRK channels, and whether chemostimulation of VTA N/OFQ neurons blunts HFD-induced binge eating. The lab also examines whether exogenous N/OFQ inhibits A10 dopamine neurons via GIRK channel activation. These mechanistic studies provide a framework for understanding clinically relevant conditions such as HIV/AIDS–related cachexia and diabetes/insulin resistance by linking molecular, synaptic, and circuit-level findings to whole-animal energy balance outcomes.

Collectively, the Wagner Laboratory’s work combines circuit-specific manipulations, sex- and diet-sensitive analyses, and translationally oriented endpoints to clarify how nociceptin/ORL1 and related neuromodulatory systems regulate energy homeostasis across physiological and pathophysiological states.