title: Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway.
abstract: Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice from high-fat diet-induced obesity and insulin resistance. On the one hand, Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beiging and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and uncoupling protein 1 (UCP1) expression. Mechanistically, fat-specific knockout of Rheb increased cAMP levels, cAMP-dependent protein kinase (PKA) activity, and UCP1 expression in subcutaneous white adipose tissue. Interestingly, treating primary adipocytes with rapamycin only partially alleviated the suppressing effect of Rheb on UCP1 expression, suggesting the presence of a novel mechanism underlying the inhibitory effect of Rheb on thermogenic gene expression. Consistent with this notion, overexpression of Rheb stabilizes the expression of cAMP-specific phosphodiesterase 4D5 (PDE4D5) in adipocytes, whereas knockout of Rheb greatly reduced cellular levels of PDE4D5 concurrently with increased cAMP levels, PKA activation, and UCP1 expression. Taken together, our findings reveal Rheb as an important negative regulator of beige fat development and thermogenesis. In addition, Rheb is able to suppress the beiging effect through an mTORC1-independent mechanism.
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Meng
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiuci
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.|Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Juli
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Sijia
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yacheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.|Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM.
authors.forename: Meilian
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China liuf@uthscsa.edu.
authors.forename: Fang
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center of Central South University, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China hu_fang98@yahoo.com.|Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000069796:Adipose Tissue, Beige / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D059305:Diet, High-Fat; D015536:Down-Regulation; D004734:Energy Metabolism / Q000235:genetics*; D005786:Gene Expression Regulation; D007333:Insulin Resistance / Q000235:genetics*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D046912:Multiprotein Complexes / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D010766:Phosphorylation; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000235:genetics
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000242:Cyclic AMP; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C531980:PDE4D protein, mouse; D020559:Monomeric GTP-Binding Proteins