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Ha, E.E.* ; Quartuccia, G.I.* ; Ling, R.* ; Xue, C.* ; Karikari, R.A. ; Hernandez-Ono, A.* ; Hu, K.Y.* ; Matias, C.V.* ; Imam, R.* ; Cui, J.* ; Pellegata, N.S. ; Herzig, S. ; Georgiadi, A. ; Soni, R.K.* ; Bauer, R.C.*

Adipocyte-specific tribbles pseudokinase 1 regulates plasma adiponectin and plasma lipids in mice.

Mol. Metab. 56:101412 (2022)

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OBJECTIVE: Multiple GWAS have identified SNPs in the 8q24 locus near TRIB1 that significantly associate with plasma lipids and other markers of cardiometabolic health, and prior studies have uncovered roles for hepatic and myeloid Trib1 in plasma lipid regulation and atherosclerosis. The same 8q24 SNPs additionally associate with plasma adiponectin levels in humans, implicating TRIB1 in adipocyte biology. Here, we hypothesize that TRIB1 in adipose tissue regulates plasma adiponectin, lipids, and metabolic health. METHODS: We investigate the metabolic phenotype of adipocyte-specific Trib1 knockout mice (Trib1_ASKO) on chow and high fat diet. Through secretomics of adipose tissue explants and RNA-seq of adipocytes and livers from these mice, we further investigate the mechanism of TRIB1 in adipose tissue. RESULTS: Trib1_ASKO mice have an improved metabolic phenotype with increased plasma adiponectin levels, improved glucose tolerance, and decreased plasma lipids. Trib1_ASKO adipocytes have increased adiponectin production and secretion independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice suggests that alterations in adipocyte function underlie the observed plasma lipid changes. Adipose tissue explant secretomics further reveals that Trib1_ASKO adipose tissue has decreased ANGPTL4 production, and we demonstrate an accompanying increase in LPL activity that likely underlies the triglyceride phenotype. CONCLUSION: Adipocyte Trib1 regulates multiple aspects of metabolic health, confirming previously observed genetic associations in humans and shedding light on further mechanisms by which TRIB1 regulates plasma lipids and metabolic health.

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