Visceral obesity associates with insulin resistance and chronic inflammation, which are major risk factors for
the metabolic syndrome, diabetes, and cardiovascular disease. Although the cellular hallmark of obesity is
neutral lipid expansion in adipocytes, adipose tissue of obese mice and humans also accumulate
macrophages and other leukocytes. It is well accepted that adipose tissue macrophages (ATMs) play a critical
role in systemic insulin resistance, suggesting that inflammatory mediators produced by ATMs are important
factors linking excess fat mass to insulin sensitivity, glucose intolerance, and increased atherosclerotic risk.
Understanding the mechanistic basis of the pro-inflammatory ATM phenotype and ATM function is required to
devise new strategies for attenuating inflammation in metabolic disease.
Pro-inflammatory pathways in ATMs are commonly attributed to classical activation (exposure to bacteria, M1),
establishing molecular links between innate immunity and metabolic dysfunction. Recent studies, including
work from our lab, suggest that M1 activation fails to accurately represent the complex phenotype of ATMs in
vivo. We have shown that ATMs in obese adipose tissue from humans and mice adopt a unique ‘metabolically
activated’ (MMe) phenotype that is distinct from the M1 phenotype. Inhibiting MMe activation of macrophages
in vivo, attenuates ATM inflammation and improved glucose tolerance in mice. Moreover, the abundance of
MMe-like ATMs in visceral fat is positively correlated with insulin resistance in patients controlled for adiposity.
These findings underscore the pathophysiological importance of MMe macrophages in mice and humans.
Although MMe and M1 macrophages are both characterized by increased expression of NFkB-induced
inflammatory cytokines (ie. Tnfa, Il1b, Il6), our preliminary studies demonstrate that the upstream signaling
cascades driving NFkB activation are remarkably distinct. We provide evidence for a novel fatty acid-driven,
ROS-dependent, tyrosine-kinase mediated, pro-inflammatory signaling cascade in MMe macrophages.
Targeting this ‘metabolically activated NFkB’ (Me-NFkB) pathway at any point selectively attenuates
inflammatory cytokine expression by MMe macrophages.
Our work has positioned us to test the innovative hypothesis that this Me-NFkB pathway promotes ATM
inflammation and insulin resistance during obesity but is dispensable for inflammation required for
host defense during infection. Specifically, we plan to 1) Delineate the Me-NFkB pathway that drives
inflammation in MMe macrophages, and 2) Determine if targeting the Me-NFkB pathway improves insulin
sensitivity in mice. Overall, our proposed studies aim to demonstrate that macrophage inflammation in
metabolic disease can be attenuated without blocking these same cytokines in bacterial infection, a conceptual
milestone that may lead to an improved anti-inflammatory strategy in the clinic.