A paradoxical but common finding in the
obesity clinic is the identification of individuals who can be considered 'inappropriately' healthy for their degree of
obesity. We think that studying these obese but metabolically healthy individuals and comparing them with equally obese but
insulin-resistant individuals could provide important insights into the mechanistic link between adipose tissue expansion and associated metabolic alterations. In the present study, we investigated whether there are differences in inflammatory and
insulin signalling pathways in VAT (visceral adipose tissue) that could account for the metabolic differences exhibited by morbidly obese individuals who are either
insulin-resistant (IR-MO) or paradoxically
insulin-sensitive (NIR-MO). Our results indicate that there are pathways common to
obesity and unrelated to
insulin resistance and others that are discriminative for
insulin resistance for a similar degree of
obesity. For instance, all morbidly obese patients, irrespective of their
insulin resistance, showed increased expression of
TNFalpha (tumour
necrosis factor alpha) and activation of JNK1/2 (
c-Jun N-terminal kinase 1/2). However, the IR-MO group showed significantly elevated expression levels of IL (interleukin)-1beta and
IL-6 and increased macrophage infiltrates compared with non-obese individuals and NIR-MO.
IkappaBalpha [inhibitor of
NF-kappaB (
nuclear factor kappaB) alpha], the activation of ERK1/2 (
extracellular-signal-regulated kinase 1/2) and
NF-kappaB were discriminative of the state of
insulin resistance and correlated with differential changes in IRS-1 (
insulin receptor substrate 1) expression and Akt activation between IR-MO and NIR-MO individuals. Our results support the concept that NIR-MO individuals lack the inflammatory response that characterizes the IR-MO patient and that
IL-6, IL-1beta, ERK and
NF-kappaB are important effectors that mediate the
inflammation effects promoting
insulin resistance.