Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

Abstract

(LT␣) is secreted by lymphocytes and acts through tumor necrosis factor-␣ receptors and the LT␤ receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT Ϫ/Ϫ ) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk. Body weight, body composition, and food intake were measured. Glucose tolerance was assessed. Systemic and adipose tissue inflammatory statuses were evaluated by quantifying plasma adipokine levels and tissue macrophage and T cell-specific gene expression in abdominal fat. LT Ϫ/Ϫ mice were smaller (20%) and leaner (25%) than WT controls after 13 wk of HFHS diet feeding. LT Ϫ/Ϫ mice showed improved glucose tolerance, suggesting that, in WT mice, LT may impair glucose metabolism. Surprisingly, adipose tissue from rodent chow-and HFHS-fed LT Ϫ/Ϫ mice exhibited increased T lymphocyte and macrophage infiltration compared with WT mice. Despite the fact that LT Ϫ/Ϫ mice exhibited an enhanced inflammatory status at the systemic and tissue level even when fed rodent chow, they were protected from enhanced diet-induced obesity and insulin resistance. Thus, LT contributes to body weight and adiposity and is required to modulate the accumulation of immune cells in adipose tissue.

Granulocyte/Macrophage Colony-stimulating Factor-dependent Dendritic Cells Restrain Lean Adipose Tissue Expansion

“…Mice were injected intraperitoneally with human insulin (1.0 unit/kg body weight; Lilly) or glucose (1 mg/g body weight) (20).…”

Lymphotoxin signalling in immune homeostasis and the control of microorganisms

“…Indeed, two groups independently demonstrated that LT-deficient animals are resistant to diet-induced obesity 96,97 . One group found that Lta −/− animals resisted excess weight gain that is induced by a high-fat diet, and that deficiency in the LT pathway resulted in increased lymphocyte infiltration into the perigonadal fat pads of animals, regardless of the diet they received 97 . In this study, the role of LTα in weight gain was considered to be redundant to that of TNF 97 .…”

“…One group found that Lta −/− animals resisted excess weight gain that is induced by a high-fat diet, and that deficiency in the LT pathway resulted in increased lymphocyte infiltration into the perigonadal fat pads of animals, regardless of the diet they received 97 . In this study, the role of LTα in weight gain was considered to be redundant to that of TNF 97 . The second study showed that animals deficient in LTα, LTβ or LTβR resisted high-fat diet-induced weight gain 96 .…”

“…Although animals lacking elements of the LT pathway resist excessive weight gain induced by a high-fat diet, they still consume similar amounts of food 96,97 . This is a unique finding because excess weight gain is driven by a positive energy imbalance induced by a high-fat diet 98 .…”

Lymphotoxin regulates commensal responses to enable diet-induced obesity

“…While the role for TNF in obesity has been extensively studied, the role that LT might play in this disease has been largely ignored. LT is essential for normal mucosal immunity 17–19 . LTα forms a membrane bound heterotrimer with LTβ and binds LTβ receptor (LTβR).…”