Lack of mature lymphocytes results in obese but metabolically healthy mice when fed a high-fat diet

Abstract

Background/Objectives: Obesity is characterized by chronic inflammation and immune dysregulation, as well as insulin resistance, but the link between obesity and adaptive immunity remains to be fully studied. Methods: To elucidate the role of adaptive immunity on body composition, glucose homeostasis, and inflammation, recombination-activating gene 1 knockout (Rag1-/-) mice, without mature T lymphocytes or B-lymphocytes, were maintained on a low (LFD) or high fat diet (HFD) for 11 weeks. Results: Rag1-/- mice fed HFD gained significantly more weight and had increased body fat compared to wild type. Downregulation of energy expenditure as well as brown fat UCP-1 and UCP-3 gene expression were noticed in HFD fed Rag1-/- mice compared to LFD. HFD mice had significantly decreased energy intake compared to LFD mice, consistent with decreased AgRP and increased POMC gene expressions in the hypothalamus. Moreover, compared to wild type, Rag1-/- mice had lower IL-4 levels, a cytokine recently found to induce browning in white adipocytes, and higher IL-12 levels in HFD fed Rag1-/- mice. Despite that HFD Rag1-/- mice were more obese, they had similar glucose, insulin, and adiponectin levels, while leptin was marginally increased. Conclusions: Mice with deficiency in adaptive immunity are obese, partly due to decreased energy expenditure, but are metabolically normal, suggesting that mature lymphocytes play necessary roles in the development of obesity-related metabolic dysregulation.