Dataset Information

Facultative protein selenation controls redox sensitivity, adipose tissue thermogenesis and obesity

ABSTRACT: Oxidation of cysteines by reactive oxygen species (ROS) initiates thermogenesis in brown and beige adipose tissues. Cellular selenols, where sulfur is replaced with selenium, exhibit enhanced reactivity with ROS. Here we developed a mass spectrometric method to interrogate incorporation of selenols into proteins. Unexpectedly, this approach revealed facultative incorporation of selenium into proteins that lack canonical encoding for selenium-containing amino acids. Selenium was selectively incorporated into regulatory sites on key metabolic proteins, including as selenocysteine replacing cysteine at position 253 in UCP1. Remarkably, dietary selenium supplementation elevated facultative incorporation into UCP1, elevated energy expenditure through thermogenic adipose tissue, and protected against obesity. Together, these findings reveal the existence of facultative protein selenation, which correlates with impacts on thermogenic adipocyte function.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brown Adipose Tissue

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: mark Jedrychowski

LAB HEAD: Edward Chouchani

PROVIDER: PXD018225 | Pride | 2021-09-09

REPOSITORIES: Pride

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Publications

Facultative protein selenation regulates redox sensitivity, adipose tissue thermogenesis, and obesity.

Jedrychowski Mark P MP Lu Gina Z GZ Szpyt John J Mariotti Marco M Garrity Ryan R Paulo Joao A JA Schweppe Devin K DK Laznik-Bogoslavski Dina D Kazak Lawrence L Murphy Michael P MP Gladyshev Vadim N VN Gygi Steven P SP Chouchani Edward T ET Spiegelman Bruce M BM

Proceedings of the National Academy of Sciences of the United States of America 20200501 20

Oxidation of cysteine thiols by physiological reactive oxygen species (ROS) initiates thermogenesis in brown and beige adipose tissues. Cellular selenocysteines, where sulfur is replaced with selenium, exhibit enhanced reactivity with ROS. Despite their critical roles in physiology, methods for broad and direct detection of proteogenic selenocysteines are limited. Here we developed a mass spectrometric method to interrogate incorporation of selenium into proteins. Unexpectedly, this approach rev ...[more]

PMID: 32358195

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Project description:Non-shivering thermogenesis in adipocytes is mediated by brown adipose tissue, purportedly through the sole action of uncoupling protein 1 (UCP1). The physiological relevance of UCP1-dependent thermogenesis has primarily been inferred from the attenuation of thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue beyond UCP1, such as reduced electron transport chain abundance. We show here that these secondary changes also encompass reduced expression of genes regulating fuel liberation, changes that would attenuate the capacity of any thermogenic pathway. Therefore, the quantitative contribution of UCP1-dependent and -independent thermogenesis is not fully understood. To mitigate the potentially confounding ancillary changes to brown adipose tissue of germline Ucp1-/- mice, we constructed mice with inducible adipocyte-selective disruption of Ucp1. We find that, while germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase B (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold-intolerance, indicative of a negative genetic interaction and thus a parallel thermogenic function. We find no evidence for impairments in insulation or non-shivering thermogenesis in skeletal muscle that would drive this phenotype. Furthermore, following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature adipocytes that coordinately restore UCP1 and CKB to brown adipose tissue, providing further evidence of their parallel thermogenic relationship. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy – through UCP1 and CKB – to promote cold-induced energy dissipation.

Dataset Information

Facultative protein selenation controls redox sensitivity, adipose tissue thermogenesis and obesity

Publications

Facultative protein selenation regulates redox sensitivity, adipose tissue thermogenesis, and obesity.

Similar Datasets

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