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ADORA1-driven brain-sympathetic neuro-adipose connections control body weight and adipose lipid metabolism

Molecular Psychiatry volume 26, pages 2805–2819 (2021)Cite this article

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Abstract

It is essential to elucidate brain-adipocyte interactions in order to tackle obesity and its comorbidities, as the precise control of brain-adipose tissue cross-talk is crucial for energy and glucose homeostasis. Recent studies show that in the peripheral adipose tissue, adenosine induces adipogenesis through peripheral adenosine A1 receptor (pADORA1) signaling; however, it remains unclear whether systemic and adipose tissue metabolism would also be under the control of central (c) ADORA1 signaling. Here, we use tissue-specific pharmacology and metabolic tools to clarify the roles of cADORA1 signaling in energy and adipocyte physiology. We found that cADORA1 signaling reduces body weight while also inducing adipose tissue lipolysis. cADORA1 signaling also increases adipose tissue sympathetic norepinephrine content. In contrast, pADORA1 signaling facilitates a high-fat diet-induced obesity (DIO). We propose here a novel mechanism in which cADORA1 and pADORA1 signaling hinder and aggravate DIO, respectively.

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Fig. 1: Central ADORA1 signaling induces expenditure and adipose lipolysis.
Fig. 2: Central ADORA1 induces adipocyte remodeling and expressions of thermogenic markers.
Fig. 3: Central ADORA1 signaling increases adipose norepinephrine (NE) content.
Fig. 4: Peripheral chronic osmotic delivery of CPA promotes body weight gain.
Fig. 5: Peripheral ADORA1 modulates adipose gene expressions.
Fig. 6: Bi-directional regulation of body weight by intra-adipose CPA or CPT injections.
Fig. 7: Anxiogenic effects of central ADORA1 stimulation.
Fig. 8: No apparent effects of peripheral CPA administration on anxiety.

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Acknowledgements

This work was supported by the NIH (R01 MH109441; R01 DK112759, to Y.Y.) and Einstein Research Foundation. We thank all the members of the Yang laboratory for discussion and critical comments on this study. We thank the Einstein Diabetes Center Animal Physiology Core for helping with indirect calorimetry studies, the Einstein Histology & Comparative Pathology Core for heling with adipose tissue histology studies, and the Einstein Diabetes Center Stable Isotope and Metabolomics Core for adipose tissue mitochondrial studies. We also thank Drs. Gary Schwartz, Streamson Chua, and Christoph Buettner for their reading and critical comments on the original version of the manuscript.

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  1. These authors contributed equally: Jia Zhang, Yanjun Hou, Xue-liang Du, Dan Chen

Authors and Affiliations

  1. Department of Medicine Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, USA

    Jia Zhang, Yanjun Hou, Xue-liang Du, Dan Chen, Guangzhi Sui & Yunlei Yang

  2. Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China

    Jia Zhang, Dan Chen & Yong Qi

  3. Departments of Psychiatry and Neuroscience, State University of New York Upstate Medical University, Syracuse, NY, USA

    Julio Licinio & Ma-Li Wong

  4. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA

    Yunlei Yang

  5. Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Yunlei Yang

  6. The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA

    Yunlei Yang

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Contributions

Y.Y. conceived and designed this study; J.Z., Y.H., D.C., and X.D. performed behavioral and metabolic studies as well as RT-qPCR assays; J.Z. and X.D. performed searhorse assays of tissue mitochondrial oxygen consumption, adipose histology, and ELISA assays; J.Z. and D.C. performed immunostaing and western blots; J.Z., X.D., and Z.G. performed indirect calorimetry studies. J.Z., D.C., G.S., and Y.H. performed mouse surgeries with cannula implantation; M.W. and Y.Y. wrote the manuscript with inputs from other authors; Q.Y., and J.L. edited the manuscript and provided experimental design suggestions.

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Correspondence to Ma-Li Wong or Yunlei Yang.

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Zhang, J., Hou, Y., Du, Xl. et al. ADORA1-driven brain-sympathetic neuro-adipose connections control body weight and adipose lipid metabolism. Mol Psychiatry 26, 2805–2819 (2021). https://doi.org/10.1038/s41380-020-00908-y

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