Facilitated By

San Antonio Medical Foundation


UT Health San Antonio

The UT Health San Antonio, with missions of teaching, research and healing, is one of the country’s leading health sciences universities.

Principal Investigator(s)
Leadbetter, Elizabeth
Funded by
Research Start Date

Obesity is a critical global epidemic, a leading cause of preventable death, and a source of skyrocketing healthcare costs. Currently more than two thirds of US adults are overweight and at least one third are consideredobese. It is increasingly appreciated that obesity is linked to chronic, low-grade inflammation in visceral adiposetissue and an associated spectrum of metabolic abnormalities including insulin resistance, fatty liver disease,and type-2 diabetes (T2D) in addition to related conditions such as heart disease, asthma, cancer, and stroke.To help control this epidemic, it will be critical to understand the specific roles of key immune cells which regulateor exacerbate inflammation and metabolic disease in obese patients. While many of the B cells resident in lean adipose tissue are IL-10-producing B regulatory cells (Breg), Bcell numbers increase in adipose tissue of obese mice and may play a role in the chronic inflammationcharacteristic of obese visceral adipose tissue (VAT). Combined alterations in B cell antigen presentation,cytokine profile, and antibody repertoire during obesity in mice and T2D in humans likely contributes to metabolicdisease by supporting T cell mediated-inflammation and insulin resistance; however, the cause of VAT B celldysregulation during obesity or T2D remains unknown. iNKT cells also make up 10-20% of T cells in healthyadipose tissue but this proportion is reduced in obese mice and humans. Activation of the remaining iNKT cellsby the glycolipid agonist, ?Galactosylceramide (?GalCer), reduces many of the inflammatory symptoms ofobesity, suggesting their loss is another important contributor to the dysregulated immune environment evidentduring obesity or related autoimmune or inflammatory diseases. We have shown that ?GalCer-activated murine iNKT cells directly interact with splenic B cells to produceantigen-specific IgG and expand IL-10+ Breg cells. Interestingly, we also see that activated iNKT cells can mediatea similar increase in IL-10+ Breg cells in VAT, suggesting they play a key role in maintaining adipose homeostasis.In a related murine model of chronic inflammation, we find that iNKT cells can also be licensed by neutrophils toregulate autoreactive B cells in spleen, but the influence of neutrophils on iNKT cells and their downstreameffects on B cells in adipose tissue remains as yet uncharacterized. We hypothesize that an early neutrophilinflux educates iNKT cells in adipose tissue of obese mice to drive a pathogenic shift from Breg to B effector cells.iNKT cell activation may also reduce metabolic disease during obesity in part by re-establishing a healthyregulatory B cell population. These studies will enhance our understanding of key regulatory immune cellpopulations in healthy and chronically inflamed obese adipose tissue with implications for many otherinflammatory diseases and related conditions such as T2D, cancer, and stroke.

Collaborative Project
Basic Research
Diabetes and Obesity