Excess nutrient consumption promotes systemic and tissue-specific inflammatory responses, inhibiting insulin
receptor signaling pathways and prevents glucose uptake. Although specific molecular and cellular mechanisms
that lead to the development of insulin resistance remain unclear, chronic inflammation is central to obesity-
induced T2D. Diet-induced adipose tissue (AT) expansion with infiltration of classically activated macrophages
and production of pro-inflammatory cytokines perpetuates chronic inflammation and insulin resistance.
Therapeutic approaches that directly interrupt innate immune responses are problematic however as they could
lead to immunosuppression and thus have limited therapeutic applicability. We have shown that persistent
inflammation in diabetes and obesity is due to a deficiency in the processes that normally resolve inflammation.
Nonetheless, mechanisms by which obesity induces perturbations in pro-resolving pathways and promote the
development of unmitigated chronic inflammation remains undefined. Physical inactivity contributes to increased
adiposity, markers of inflammation, chronic disease, and premature death, while physical activity protects against
the development of obesity and chronic inflammation independent of reductions in weight. Cellular mechanisms
by which physical activity protects against chronic inflammation, however, remain largely unknown. Recent work
has shown that resolution of inflammation is mediated in part by enzymatic (15-,12-, 5-lipoxygenase, and
cyclooxygenases) conversion of polyunsaturated fatty acids into specialized proresolving lipid mediators (SPMs;
e.g., resolvins, lipoxins, maresins, and protectins) that act to quell inflammatory signaling. Importantly, our lab
and others have also shown that obese-diabetic mice treated with SPMs display elevated alternatively activated
macrophages with reduced AT inflammation, improved insulin sensitivity, and enhanced wound healing capacity.
Additionally, our lab has shown that high fat diet-induced insulin resistance develops due to elevated pro-
inflammatory lipid mediator leukotriene B4 (LTB4) production and that BLT-1 (LTB4 receptor) deficient mice are
protected against diet-induced insulin resistance— a paradigm that also persists in atherosclerotic lesions. These
findings suggest that imbalanced production of pro-inflammatory and proresolving lipid mediators contribute to
obesity-induced insulin resistance. Our preliminary data show that exercise increases AT SPM biosynthesis and
is inhibited by short duration high fat diet (HFD) feeding. We also find that HFD inhibits exercise-induced
alternatively activated adipose tissue macrophages (ATM) levels. Interestingly, adrenal gland expression of
biosynthetic enzymes and catecholamine levels—which our lab has previously shown to stimulate SPM
biosynthesis in macrophages—are reduced following HFD feeding. Thus, we hypothesize that HFD-induced
adrenergic dysfunction inhibits the proresolving response to exercise in AT. In pursuit of the scientific questions
herein, I will hone my basic laboratory skills, learn advanced techniques, develop professional skills and network,
all of which will propel me towards achieving my goal of becoming an independent investigator in academia.