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other·preclinical research, biomedical research, neurology, endocrinology·PMC10159165

Diurnal regulation of metabolism by G s -alpha in hypothalamic QPLOT neurons

PLOS ONE · 11 authors, 10 centres

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TL;DR

This preclinical study used genetically modified mice to show that removing G s-alpha signaling from a specific set of hypothalamic neurons (QPLOT neurons) decreased nighttime movement and altered daily metabolic rhythms, particularly at cooler temperatures.

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Researchers investigated the role of the stimulatory G-protein subunit G s-alpha (encoded by *Gnas*) in hypothalamic preoptic area (POA) QPLOT neurons in regulating metabolism. Using *Opn5*^*cre*^*; Gnas*^*fl/fl*^ mice and indirect calorimetry, they assessed energy expenditure, respiratory exchange, food/water intake, and locomotion at thermoneutral (28°C), standard (22°C), and cold (10°C) temperatures. The primary finding was a marked decrease in nocturnal locomotion at 28°C and 22°C. Circadian analysis revealed subtle rhythmic changes, including a higher rhythm-adjusted mean energy expenditure at 22°C and 10°C, a significant phase delay in energy expenditure and respiratory exchange at 28°C, and a temperature-dependent shift in respiratory exchange rhythm. The study is limited by the use of a mouse model, potential incomplete genetic deletion, and the fact that specific receptors mediating these effects were not identified. The findings advance understanding of how G s-alpha signaling in POA neurons contributes to the daily patterning of metabolic processes in a mouse model.

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other

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preclinical research

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ORIGINAL PAPER

PMC10159165

Diurnal regulation of metabolism by G s -alpha in hypothalamic QPLOT neurons

PLOS ONE

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ABSTRACT

Abstract Neurons in the hypothalamic preoptic area (POA) regulate multiple homeostatic processes, including thermoregulation and sleep, by sensing afferent input and modulating sympathetic nervous system output. The POA has an autonomous circadian clock and may also receive circadian signals indirectly from the suprachiasmatic nucleus. We have previously defined a subset of neurons in the POA termed QPLOT neurons that are identified by the expression of molecular markers ( Qrfp , Ptger3 , LepR , Opn5 , Tacr3 ) that suggest receptivity to multiple stimuli. Because Ptger3 , Opn5 , and Tacr3 encode G-protein coupled receptors (GPCRs), we hypothesized that elucidating the G-protein signaling in these neurons is essential to understanding the interplay of inputs in the regulation of metabolism. Here, we describe how the stimulatory G s -alpha subunit ( Gnas ) in QPLOT neurons regulates metabolism in mice. We analyzed Opn5 cre ; Gnas fl/fl mice using indirect calorimetry at ambient temperatures of 22°C (a historical standard), 10°C (a cold challenge), and 28°C (thermoneutrality) to assess the ability of QPLOT neurons to regulate metabolism. We observed a marked decrease in nocturnal locomotion of Opn5 cre ; Gnas fl/fl mice at both 28°C and 22°C, but no overall differences in energy expenditure, respiratory exchange, or food and water consumption. To analyze daily rhythmic patterns of metabolism, we assessed circadian parameters including amplitude, phase, and MESOR. Loss-of-function GNAS in QPLOT neurons resulted in several subtle rhythmic changes in multiple metabolic parameters. We observed that Opn5 cre ; Gnas fl/fl mice show a higher rhythm-adjusted mean energy expenditure at 22°C and 10°C, and an exaggerated respiratory exchange shift with temperature. At 28°C, Opn5 cre ; Gnas fl/fl mice have a significant delay in the phase of energy expenditure and respiratory exchange. Rhythmic analysis also showed limited increases in rhythm-adjusted means of food and water intake at 22°C and 28°C. Together, these data advance our understanding of G αs -signaling in preoptic QPLOT neurons in regulating daily patterns of metabolism.

CITATION EXPORT

Kevin D Gaitonde, Mutahar Andrabi, Courtney A Burger et al.. Diurnal regulation of metabolism by Gs-alpha in hypothalamic QPLOT neurons. PLOS ONE. (2023). https://doi.org/10.1371/journal.pone.0284824

AUTHORS

11 · 10 CENTRES

Kevin D Gaitonde, Mutahar Andrabi, Courtney A Burger, Shane P D’Souza, Shruti Vemaraju, Bala S C Koritala, David F Smith, Richard A Lang, Nicholas Simon Foulkes, Nicholas Simon Foulkes, Nicholas Simon Foulkes

1Division of Pediatric Ophthalmology, Abrahamson Pediatric Eye Institute, Visual Systems Group, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States of America
2Science of Light Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States of America
3Molecular & Developmental Biology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America
4Medical Scientist Training Program, University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America
5Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH, United States of America
6Division of Pediatric Otolaryngology–Head and Neck Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States of America
7Department of Otolaryngology–Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
8Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States of America
9The Center for Circadian Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States of America
10Karlsruhe Institute of Technology, GERMANY