Genetic deletion of Rheb1 in the brain reduces food intake and causes hypoglycemia with altered peripheral metabolism.
Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral metabolism need to be better understood for developing pharmacological interventions to manage eating behavior and obesity. Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a master regulator of cellular metabolism in different cell types. Pharmacological manipulations of mTOR complex 1 (mTORC1) activity in hypothalamic neurons alter food intake and body weight. Our previous study identified Rheb1 (Ras homolog enriched in brain 1) as an essential activator of mTORC1 activity in the brain. Here we examine whether central Rheb1 regulates food intake and peripheral metabolism through mTORC1 signaling. We find that genetic deletion of Rheb1 in the brain causes a reduction in mTORC1 activity and impairs normal food intake. As a result, Rheb1 knockout mice exhibit hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver. Our work highlights the importance of central Rheb1 signaling in euglycemia and energy homeostasis in animals.
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. yangwanchunscu@gmail.com.
Wanchun
W
Yang
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. wanxjiang@gmail.com.
Wanxiang
W
Jiang
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. lipingluo1987@gmail.com.
Liping
L
Luo
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. jichengbu@gmail.com.
Jicheng
J
Bu
West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, China. pangdejiang@gmail.com.
Dejiang
D
Pang
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. weijing3131@gmail.com.
Jing
J
Wei
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. duchongyangzi@gmail.com.
Chongyangzi
C
Du
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. xiaoqiangxia@gmail.com.
Xiaoqiang
X
Xia
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. cuiyy307@gmail.com.
Yiyuan
Y
Cui
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China. liushuang3302@163.com.
Shuang
S
Liu
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China. qingmao2000@163.com.
Qing
Q
Mao
Laboratory of Molecular Neurobiology, State Key Laboratory of Biotherapy/West China Hospital, Sichuan University, Chengdu 610041, China. chenmina2010@gmail.com.
Mina
M
Chen
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism*; D004435:Eating / Q000235:genetics*; D017353:Gene Deletion; D006706:Homeostasis; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins