Crosstalk between corepressor NRIP1 and cAMP signaling on adipocyte thermogenic programming.

Objectives: Nuclear receptor interacting protein 1 (NRIP1) suppresses energy expenditure via repression of nuclear receptors, and its depletion markedly elevates uncoupled respiration in mouse and human adipocytes. We tested whether NRIP1 deficient adipocytes implanted into obese mice would enhance whole body metabolism. Since β-adrenergic signaling through cAMP strongly promotes adipocyte thermogenesis, we tested whether the effects of NRIP1 knock-out (NRIP1KO) require the cAMP pathway.
Methods: NRIP1KO adipocytes were implanted in recipient high-fat diet (HFD) fed mice and metabolic cage studies conducted. The Nrip1 gene was disrupted by CRISPR in primary preadipocytes isolated from control vs adipose selective GsαKO (cAdGsαKO) mice prior to differentiation to adipocytes. Protein kinase A inhibitor was also used.
Results: Implanting NRIP1KO adipocytes into HFD fed mice enhanced whole-body glucose tolerance by increasing insulin sensitivity, reducing adiposity, and enhancing energy expenditure in the recipients. NRIP1 depletion in both control and GsαKO adipocytes was equally effective in upregulating uncoupling protein 1 (UCP1) and adipocyte beiging, while β-adrenergic signaling by CL 316,243 was abolished in GsαKO adipocytes. Combining NRIP1KO with CL 316,243 treatment synergistically increased Ucp1 gene expression and increased the adipocyte subpopulation responsive to beiging. Estrogen-related receptor α (ERRα) was dispensable for UCP1 upregulation by NRIPKO.
Conclusions: The thermogenic effect of NRIP1 depletion in adipocytes causes systemic enhancement of energy expenditure when such adipocytes are implanted into obese mice. Furthermore, NRIP1KO acts independently but cooperatively with the cAMP pathway in mediating its effect on adipocyte beiging.
Competing Interests: Declaration of competing interest The authors declare the following competing Interests: M.P.C. and A.G. are inventors of granted US Patent US-8519118-B2, “RIP140 regulation of glucose transport”, and of granted US Patent US-8093223-B2, “RIP140 regulation of diabetes”, related to data in this manuscript on Nrip1/RIP140-depleted mouse and human adipocytes. M.P.C., E.T., and S.M.N. are inventors of US Patent US-20220220461-A1 and PCT WO2022076812A3, “Targeting Nrip1 to Alleviate Metabolic Disease”, related to CRISPR-based depletion of NRIP1 in mouse adipocytes in this manuscript. The University of Massachusetts is the grantee or potential grantee of all the above. M.P.C. declares that he is bound by a confidentiality agreement that prevents him from disclosing a potentially competing interest in this work. S.A.W. is a consultant for Chroma Medicine. The remaining authors declare no competing interests.
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