Macrophage Proliferation Sustains Adipose Tissue Inflammation in Formerly Obese Mice

Author:

Zamarron Brian F.1ORCID,Mergian Taleen A.2,Cho Kae Won3,Martinez-Santibanez Gabriel4,Luan Danny2,Singer Kanakadurga15ORCID,DelProposto Jennifer L.5,Geletka Lynn M.5,Muir Lindsey A.5ORCID,Lumeng Carey N.145ORCID

Affiliation:

1. Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI

2. College of Literature Sciences and Arts, University of Michigan, Ann Arbor, MI

3. Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do, Korea

4. Department of Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI

5. Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI

Abstract

Obesity causes dramatic proinflammatory changes in the adipose tissue immune environment, but relatively little is known regarding how this inflammation responds to weight loss (WL). To understand the mechanisms by which meta-inflammation resolves during WL, we examined adipose tissue leukocytes in mice after withdrawal of a high-fat diet. After 8 weeks of WL, mice achieved similar weights and glucose tolerance values as age-matched lean controls but showed abnormal insulin tolerance. Despite fat mass normalization, total and CD11c+ adipose tissue macrophage (ATM) content remained elevated in WL mice for up to 6 months and was associated with persistent fibrosis in adipose tissue. ATMs in formerly obese mice demonstrated a proinflammatory profile, including elevated expression of interferon-γ, tumor necrosis factor-α, and interleukin-1β. T-cell–deficient Rag1−/− mice showed a degree of ATM persistence similar to that in WT mice, but with reduced inflammatory gene expression. ATM proliferation was identified as the predominant mechanism by which ATMs are retained in adipose tissue with WL. Our study suggests that WL does not completely resolve obesity-induced ATM activation, which may contribute to the persistent adipose tissue damage and reduced insulin sensitivity observed in formerly obese mice.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

American Diabetes Association

National Institute of Allergy and Infectious Diseases

American Heart Association

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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