Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-KOSF-1) using steroidogenic factor 1-Cre (SF-1-Cre) or injecting an adenoassociated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-KOSF-1 and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.
Bibliographical noteFunding Information:
We thank Joel K. Elmquist (University of Texas Southwestern Medical Center, Dallas, Texas, USA) for kindly providing us with the SF-1–Cre mice. We also thank Andrew Shin (Texas Tech University, Lubbock, Texas, USA), Alexandre Caron (University of Texas Southwestern Medical Center), and Jessica Hong (Brown University, Providence, Rhode Island, USA) for critical reading of the manuscript. This work was supported by the National Research Foundation, Korea (2016R1C1B3012748, 2020M3E5E2038221, and 2016R1A5A2008630 to KWK; 2015H1A2A1032009 to DJY; 2013M3A9D5072550 to JKS). This research was also supported by a grant from the Korean Diabetes Association (2018F-1 to KWK).
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