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. 2020 Apr;34:112-123.
doi: 10.1016/j.molmet.2020.01.008. Epub 2020 Jan 22.

Functional Loss of Inactive Rhomboid-Like Protein 2 Mitigates Obesity by Suppressing Pro-Inflammatory Macrophage Activation-Triggered Adipose Inflammation

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Free PMC article

Functional Loss of Inactive Rhomboid-Like Protein 2 Mitigates Obesity by Suppressing Pro-Inflammatory Macrophage Activation-Triggered Adipose Inflammation

Minxuan Xu et al. Mol Metab. .
Free PMC article

Abstract

Objective: Chronic inflammation of adipose tissues contributes to obesity-triggered insulin resistance. Unfortunately, the potential molecular mechanisms regarding obesity-associated systemic inflammation and metabolic disorder remain complicated. Here, we report that inactive rhomboid-like protein 2 (iRhom2) was increased in overweight mice with adipose inflammation.

Methods: Mice with deletion of iRhom2 on a C57BL/6J background, mice without deletion of this gene (controls), and mice with deficiency of iRhom2 only in myeloid cells were fed a standard chow diet (SCD) or a high-fat diet (HFD; 60% fat calories). Then the adipose tissues or bone marrow cells were isolated for the further detection.

Results: After 16 weeks on a high-fat diet (HFD), obesity, chronic inflammation in adipose tissues, and insulin resistance were markedly mitigated in iRhom2 knockout (iRhom2 KO) mice, whereas these parameters were exaggerated in iRhom2 overactivated mice. The adverse influences of iRhom2 on adipose inflammation and associated pathologies were determined in db/db mice. We further demonstrated that, in response to an HFD, iRhom2 KO mice and mice with deletion only in the myeloid cells showed less severe adipose inflammation and insulin resistance than control groups. Conversely, transplantation of bone marrow cells from normal mice to iRhom2 KO mice unleashed severe systemic inflammation and metabolic dysfunction after HFD ingestion.

Conclusion: We identified iRhom2 as a key regulator that promotes obesity-associated metabolic disorders. Loss of iRhom2 from macrophages in adipose tissues may indirectly restrain inflammation and insulin resistance via blocking crosslinks between macrophages and adipocytes. Hence, iRhom2 may be a therapeutic target for obesity-induced metabolic dysfunction.

Keywords: Adipose inflammation; Dyslipidemia; Insulin resistance; iRhom2.

Figures

Image 1
Figure 1
Figure 1
iRhom2 increases in adipose tissues and promotes adipose inflammation in obese mice. (A) Western blotting for the expression of iRhom2, TNFR1/2, TNF-α, and phosphorylated NF-κB in iWAT harvested from standard chow diet and high-fat diet-fed C57BL/6N mice. (B) Western blotting of isolated adipocytes in iWAT of SCD and HFD-fed C57BL/6N mice. (C) qPCR expression changes in iRhom2, TNFR1/2, and TNF-α from iWAT or adipocytes in SCD and HFD-fed C57BL/6N mice; n = 6. (D) Western blotting of iWAT from db/db and corresponding mice. The data are expressed as mean ± SEM, *p < 0.05.
Figure 2
Figure 2
iRhom2 deficiency exhibits decreased fat mass and insulin resistance. (A) Body weight of male C57BL/6N WT and iRhom2 KO mice during SCD and HFD feeding, n = 15. (B) Fat mass and (C) lean mass in male C57BL/6N WT and iRhom2 KO mice with SCD and HFD feeding, n = 15. (D) Representative photos of HFD-fed WT mice, iRhom2 KO mice, appearance of the liver, and Oil Red O stained hepatic sections (100× magnification). (E) Representative immunoblot bands of the levels of insulin resistance-associated signaling expression including phosphorylated IRS1Y608, AKT, GSK3β, FOXO1, and PEPCK in iWAT and eWAT from HFD-fed WT and iRhom2 KO mice. (F) Glucose tolerance test and (G) insulin tolerance test of HFD or SCD-fed WT and iRhom2 KO mice, n = 15. The data are expressed as mean ± SEM. *p < 0.05 vs iRhom2 KO/HFD. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Figure 3
Figure 3
iRhom2 contributes to adipose inflammatory responses in obese mice. (A) Representative immunoblot bands of the expression of inflammation-related signaling including TNFR1/2, phosphorylated IκBα, NF-κB, TAK1, and TNF-α. qPCR analysis detection of the mRNA expression of the genes responsible for (B) lipid metabolism and (C) inflammatory cytokines and chemokines in HFD-fed WT and iRhom2 mice, n = 6. Representative western blotting bands of the expression of inflammatory signaling in (D) adipocytes and (E) F4/80 ± macrophages isolated from iWAT of HFD-fed WT and iRhom2 mice. (F) Western blotting analysis of inflammatory signaling in iWAT of HFD-fed AAV-iRhom2 overactivated and corresponding mice. mRNA expression of the genes responsible for (G) lipid metabolism and (H) inflammatory cytokines and chemokines in HFD-fed AAV control and AAV-iRhom2 overactivated mice, n = 6. Western blotting of the expression of inflammation indicators in (I) adipocytes and (J) F4/80 ± macrophages from iWAT of AAV control and AAV-iRhom2 overactivated mice. The data are expressed as mean ± SEM, *p < 0.05.
Figure 4
Figure 4
Myeloid cell-specific iRhom2 deletion downregulates insulin resistance and inflammation in obese mice. (A) Body weight was examined before and after the feeding period, n = 15. (B) Body composition, n = 10. (C) Glucose and (D) insulin tolerance test, n = 15. Western blotting bands of the expression of (E) insulin signaling from iWAT and (F) inflammation signaling of F4/80+ macrophages in iWAT. mRNA expression of the genes responsible for (G) lipid metabolism and (H) inflammatory cytokines and chemokines in HFD-fed WTBM→WT/HFD and KOBM→WT/HFD mice, n = 6. The data are expressed as mean ± SEM, *p < 0.05.
Figure 5
Figure 5
A schematic diagram demonstrating the possible role of iRhom2 in high-fat diet-induced adipose inflammation and insulin resistance.

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