Naa10P puts a brake on PGC1α and fat browning

Wang, Qiang; Kajimura, Shingo

doi:10.1038/s41594-019-0310-2

Cited by 2 publications

(2 citation statements)

References 7 publications

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“…A recent study showed that N-α-acetyltransferase 10 protein (NAA10) catalyzes the N-terminal acetylation of PGC1α and inhibits PGC1α activity by preventing its recruitment to the Ucp1 promoter [20]. However it is not yet known whether N-α-acetylation of PGC1α is reversible and how it is regulated [21].…”

Section: Introductionmentioning

confidence: 99%

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

Shi

Silva

Liu

et al. 2022

Preprint

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Norepinephrine stimulates the adipose tissue thermogenic program through a beta-adrenergic receptor (Beta AR) - cyclic adenosine monophosphate (cAMP) - protein kinase A (PKA) signaling cascade. Previous work from our lab showed that noncanonical activation of the mechanistic target of rapamycin complex 1 (mTORC1) by PKA is required for the beta AR-stimulation of adipose tissue browning. However, the downstream events triggered by mTORC1 activation that drive this thermogenic response are not well understood. In this study, we used a proteomic approach of Stable Isotope Labeling by/with Amino acids in Cell culture (SILAC) to characterize the global protein phosphorylation profile in brown adipocytes with beta-agonist isoproterenol stimulation and identified salt-inducible kinase 3 (SIK3) as a candidate mTORC1 substrate. SIK3 interacts with RAPTOR, the defining component of the mTORC1 complex, and is phosphorylated at Ser 884 in a mTORC1-dependent manner. Pharmacological SIK inhibition by a pan-SIK inhibitor (HG-9-91-01) in brown adipocytes increases basal Ucp1 gene expression and restores its expression upon either mTORC1 or PKA blockades. Short-hairpin RNA knockdown of Sik3 augments, while overexpression of SIK3 suppresses, Ucp1 gene expression in brown adipocytes. In addition, CRISPR gene-edited Sik3-/- brown adipocytes show enhanced Ucp1 gene expression at basal conditions and after Iso stimulation. Finally, a SIK inhibitor well-tolerated in vivo (YKL-05-099) can stimulate adipose tissue browning and thermogenic gene expression in mouse subcutaneous inguinal adipose tissue, supporting an essential role of SIK inhibition in regulating the adipose tissue browning program in vivo. Taken together, our data reveal that salt-inducible kinases function as a phosphorylation switch for beta-adrenergic activation to drive the adipose thermogenic program and suggest that maneuvers targeting SIKs could be beneficial for obesity and related metabolic disease.

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Section: Introductionmentioning

confidence: 99%

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

Shi

Silva

Liu

et al. 2022

Preprint

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“…Additionally, brown adipocytes are characterized by their high mitochondrial content and expression of uncoupling protein 1 (UCP1) (17,18). Lastly, beige adipocytes are located within subcutaneous WAT depots, and are derived from precursor cells upon environmental cues such as cold exposure, through a process known as "browning" (16,19,20). Interestingly, although beige adipocytes have a lower basal expression of UCP1 relative to brown adipocytes, it has been demonstrated that their thermogenic capacity can be raised to levels comparable to that of brown adipocytes upon stimulation (19).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

et al. 2020

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Over the past decade, the increasing prevalence of obesity and its associated metabolic disorders constitutes one of the most concerning healthcare issues for countries worldwide. In an effort to curb the increased mortality and morbidity derived from the obesity epidemic, various therapeutic strategies have been developed by researchers. In the recent years, advances in the field of adipocyte biology have revealed that the thermogenic adipose tissue holds great potential in ameliorating metabolic disorders. Additionally, epigenetic research has shed light on the effects of histone acetylation on adipogenesis and thermogenesis, thereby establishing the essential roles which histone acetyltransferases (HATs) and histone deacetylases (HDACs) play in metabolism and systemic energy homeostasis. In regard to the therapeutic potential of thermogenic adipocytes for the treatment of metabolic diseases, herein, we describe the current state of knowledge of the regulation of thermogenic adipocyte differentiation and adaptive thermogenesis through histone acetylation. Furthermore, we highlight how different HATs and HDACs maintain the epigenetic transcriptional network to mediate the pathogenesis of various metabolic comorbidities. Finally, we provide insights into recent advances of the potential therapeutic applications and development of HAT and HDAC inhibitors to alleviate these pathological conditions.

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Naa10P puts a brake on PGC1α and fat browning

Cited by 2 publications

References 7 publications

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

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