Dissertation
The role of central RGS2 in the regulation of energy homeostasis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2022
DOI: 10.25820/etd.006778
Abstract
Extensive evidence indicates that multiple G protein-coupled receptors (GPCRs) within distinct neuronal populations are crucial for maintaining metabolic homeostasis. Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein that modulates GPCR-Gα signaling and mice lacking RGS2 globally exhibit metabolic alterations. While RGS2 is known to be broadly expressed throughout the body including the brain, the relative contribution of brain RGS2 to metabolic homeostasis remains unknown.
Our studies showed that Rgs2 mRNA is widely expressed throughout the mouse brain, with the highest expression being observed in the paraventricular nucleus of hypothalamus (PVN) along with several other brain regions, such as the arcuate nucleus of hypothalamus and the dorsal raphe nucleus. Within the PVN, we found that Rgs2 is specifically enriched in CRH+ endocrine neurons and is further increased by calorie restriction. Functionally, although Sim1-Cre-mediated prenatal deletion of Rgs2 (Rgs2Sim1-KO) in PVN neurons had no major effects on metabolic homeostasis, AAV-mediated adult deletion of Rgs2 in the PVN led to significantly increased food intake, body weight (both fat and fat-free masses), body length, and blood glucose levels in both male and female mice. Strikingly, we found that prolonged postnatal loss of Rgs2 leads to neuronal cell death in the PVN, while rapid body weight gain in the early phase of viral-mediated PVN Rgs2 deletion is independent of PVN neuronal loss. These results provide the first evidence to support the role of PVN RGS2 in the regulation of whole-body energy metabolism.
Interestingly, we found that Rgs2 mRNA and melanocortin 4 receptor (MC4R) reporter co-expressed in several hypothalamic nuclei, including PVN, which led to a hypothesis that RGS2 impact whole-body energy homeostasis through modulating MC4R signaling. We then generated mice lacking Rgs2 specifically in MC4R-expressing cells (Rgs2MC4R-KO mice). Metabolic phenotyping revealed that both male and female Rgs2MC4R-KO mice gain significantly more weight than control littermates with sex-biased alteration in body composition and RER. Strikingly, Rgs2MC4R-KO mice have comparable food intake, energy expenditure, and digestive efficiency with that of control littermates. Rgs2MC4R-KO mice display a partially blunted anorectic response to the systemic treatment of an FDA-approved anti-obesity medication setmelanotide (MC4R agonist) but retain an intact brown adipose tissue thermogenic response to cold exposure or setmelanotide treatment. Collectively, our results demonstrate that RGS2 expression in MC4R+ neurons is required for the homeostatic regulation of energy balance – the effect is likely independent of MC4R signaling.
In all, my studies showed that central RGS2 is a critical regulator of metabolic homeostasis. Given the importance of hypothalamic GPCR signaling pathways for the development of anti-obesity medications as well as the known role of RGS2 in modulating GPCR-Gα signaling, our findings support RGS2 as a potential molecular candidate which could be targeted to develop a novel therapeutic approach for obesity.
Details
- Title: Subtitle
- The role of central RGS2 in the regulation of energy homeostasis
- Creators
- Yue Deng
- Contributors
- Huxing Cui (Advisor)Deniz Atasoy (Committee Member)Rory A. Fisher (Committee Member)Kamal Rahmouni (Committee Member)Julien A. Sebag (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacology
- Date degree season
- Autumn 2022
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006778
- Number of pages
- xiv, 124 pages
- Copyright
- Copyright 2022 Yue Deng
- Language
- English
- Description illustrations
- Illustrations, charts, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 108-124).
- Public Abstract (ETD)
Obesity, a consequence of chronic positive energy balance, has become a major public health concern due to its high risk of developing life-threatening chronic diseases including diabetes, hypertension, and certain types of cancer. While it is known that the central nervous system (CNS) plays a major role in this pathological process, the underlying neural substrates remain incompletely understood. In addition, current pharmacotherapies are limited by efficacy and/or side effects, thus identification of novel regulatory pathways would be beneficial for the development of new anti-obesity drugs.
Previous studies found that regulator of G protein signaling 2 (RGS2) is involved in the regulation of whole-body energy balance. We showed that RGS2 is widely expressed in the brain and is enriched in several brain regions that are critical for maintaining normal energy balance. We demonstrated that postnatal loss of RGS2 in the paraventricular nucleus of hypothalamus (PVN) lead to obesity phenotypes and death of PVN neurons. In addition, we found that conditional deletion of RGS2 in cells expressing melanocortin 4 receptor (MC4R), another critical regulator of energy balance, also lead to obesity phenotypes in mice. Moreover, these conditional RGS2 knockout mice had blunted responses to the anorectic effect of setmelanotide, an FDA-approved anti-obesity drug that activates MC4R signaling. Our data highlights that central RGS2 plays an important role in the regulation of energy balance, supporting RGS2 as a potential molecular candidate which could be targeted to develop a novel therapeutic approach for obesity.
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9984362958802771
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