Neuromodulation of orexin neurons reduces diet-induced adiposity

Abstract

Background/Objectives Low levels of orexin are associated with obesity and reduced physical activity in humans and animals. Subjects/Methods Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) selectively activated orexin neurons in mouse lateral hypothalamus (LH) to measure effects on spontaneous physical activity (SPA). DREADD targeting was achieved by stereotaxic injection of AAV vectors into caudal lateral LH of heterozygous orexin Cre or C57/B6J mice. In one set of studies, excitation of orexin neurons was examined (virus: AAV2-EF1a-DIO-hM3Dq-mCherry), and test sessions began 3–4 h after light cycle onset. In a study examining the inhibition of orexin neurons (virus: AAV2-hSyn-DIO-hM4Di-mCherry), testing began 15 minutes prior to dark cycle onset. Clozapine n-oxide (CNO; 1 or 5 mg/kg) or saline was injected intraperitoneally and time spent moving in open field chambers was recorded for 2 h. Follow-up studies in separate mice cohorts quantified SPA in parallel with changes in energy expenditure (EE) and chow intake using indirect calorimetry chambers (SableSystem™). Following acclimation, testing sessions (saline and/or CNO) took place over the course of ~1 week, with injections administered every day. Changes in SPA, EE, chow intake, fecal boli, and body composition (EchoMRI™) were measured. Additional mice cohorts were fed a high-fat diet (HFD) and injected with CNO daily up to 10 days to assess the potential for orexin activation to prevent diet-induced obesity. Results Activation of orexin resulted in increases in SPA in male and female mice, and was accompanied by increases in energy expenditure without changes in overall chow intake. When orexin activation occurred in the context of high fat diet, weight gain and adiposity were significantly attenuated. SPA was decreased when DREADDs were used to inhibit orexin activity. Conclusion These results demonstrate that orexin neurons play a critical role in mediating physical activity and suggest a novel therapeutic target for treating obesity.

Spontaneous Physical Activity Defends Against Obesity

“…In this way, we are able to activate only these specific orexin neurons with the designer drug. Using this method, we showed increases in SPA and NEAT by once daily administration of CNO, and prevention of adiposity gain in mice given a high fat diet [96]. Importantly, these data demonstrate strong proof-of-concept that stimulation of SPA and NEAT through orexin neurons can be used therapeutically to prevent adiposity and obesity.…”

“…Expression of DREADDs can be genetically restricted to orexin neurons using a Cre-lox system, in which the DNA recombinase, Cre, is excised and re-orients the genetic material encoding DREADDs so that transcription can proceed. In a recent publication by our group [96] we used transgenic (Orexin-Cre) mice in which expression of Cre is under the control of the orexin promoter. We further restricted the area of stimulation by use of orexin-Cre mice in combination with a stereotaxically controlled viral DREADD delivery to express specific regulation only in orexin neurons within the lateral portion of the lateral hypothalamus.…”

Chronic Chemogenetic Manipulation of Ventral Pallidum Targeted Neurons in Rats Fed an Obesogenic Diet

“…Both human ventral striatal DBS in a patient with obsessive compulsive disorder and optogenetic activation of dopamine D1 receptor neurons in nucleus accumbens of mice have been shown to increase glucose tolerance and insulin sensitivity [55]. Manipulation of lateral hypothalamic neuronal populations are known to alter both basal metabolic rate and spontaneous physical activity [56] and could be possible mediators of our DREADD manipulation by altering energy homeostatic processes that produced the observed weight changes.…”

Obesity and Related Type 2 Diabetes: A Failure of the Autonomic Nervous System Controlling Gastrointestinal Function?

“…By modulating the activity of their receptors with a synthetic ligand (RASSL) or with drugs active exclusively on designer drug receptors (DREADD), control of their signaling is gained [131]. DREADDs are a form of pharmacosynthetic (or chemogenetic) long-acting neuromodulator [132]. They depend on the G-protein-coupled receptors that are modified to lose affinity for their biological ligand and obtain a powerful activation by a synthetic drug.…”