Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity

Abstract

Background Obesity is associated with impaired primary and secondary immune responses to influenza infection, with T cells playing a critical role. T-cell function is highly influenced by the cellular metabolic state; however, it remains unknown how altered systemic metabolism in obesity alters T-cell metabolism and function to influence immune response. Our objective was to identify the altered cellular metabolic state of T cells from obese mice so that we may target T-cell metabolism to improve immune response to infection. Methods Mice were fed normal chow or high-fat diet for 18-19 weeks. Changes in T-cell populations were analyzed in both adipose tissue and spleens using flow cytometry. Splenic T cells were further analyzed for nutrient uptake and extracellular metabolic flux. As changes in T-cell mitochondrial oxidation were observed in obesity, obese mice were treated with metformin for 6 weeks and compared to lean control mice or obese mice undergoing weight loss through diet switch; immunity was measured by survival to influenza infection. Results We found changes in T-cell populations in adipose tissue of high-fat diet-induced obese mice, characterized by decreased proportions of Treg cells and increased proportions of CD8 + T cells. Activated CD4 + T cells from obese mice had increased glucose uptake and oxygen consumption rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose. Treatment of isolated CD4 + T cells with metformin was found to inhibit OCR in vitro and alter the expression of several activation markers. Last, treatment of obese mice with metformin, but not weight loss, was able to improve survival to influenza in obesity. Conclusions T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, which can be targeted to improve survival against influenza infection.

The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease

“…However, Treg cells are decreased in dietinduced obesity, which is consistent with the role of leptin in inhibiting Treg cell proportions, given that leptin levels are elevated in this setting (68). Treg cell proportions are also specifically decreased in the adipose tissue in diet-induced obesity, where leptin levels are expected to be highest (69). On the other hand, leptin mutant ob/ob mice were shown to have increased peripheral Foxp3+ CD4 + Treg cells compared to WT mice, further supporting the role of leptin, and not obesity alone, in decreasing Treg cell proportions (67).…”

Bacterial factors required for Streptococcus pneumoniae coinfection with influenza A virus

“…In addition, the metabolic reprogramming associated with influenza infection in adipose tissue and preadipocytes promotes influenza virus replication [38]. Therefore, obesity, which changes the T-cell metabolome, is a risk factor for increased mortality from influenza infection [39]. Accordingly, the effects of the metabolome changes that occur with influenza infection, which may increase the incidence of secondary bacterial infection, are worthy of further study.…”

Dysregulated Inflammation During Obesity: Driving Disease Severity in Influenza Virus and SARS-CoV-2 Infections

“…Metformin also improved the survival of obese mice in IAV infection (288). Mechanistically, this was attributed to metformin normalizing CD4+ T cell glucose oxidation and therefore function in the obese mice, though it is likely metformin has a positive effect on multiple immune cell populations (288). Interestingly, this study compared metformin treatment to a weight loss treatment group, which was not sufficient to reverse the obesity-related effects on CD4+ T cells, or improve survival, suggesting long lasting immune alterations.…”

“…Metformin decreases mitochondrial oxidation and is primarily prescribed as a drug to treat Type 2 Diabetes. Metformin also improved the survival of obese mice in IAV infection (288). Mechanistically, this was attributed to metformin normalizing CD4+ T cell glucose oxidation and therefore function in the obese mice, though it is likely metformin has a positive effect on multiple immune cell populations (288).…”