Nutrient excess, weight gain, and ensuing obesity result in expansion of adipose tissue mass and adipocyte size. With this expansion, total free fatty acid release into the circulation is increased and oxygen delivery to the adipocyte is decreased. The combination of microhypoxia and nutrient excess leads to induction of HIF-1 and the downstream target genes as well as ER stress within the adipocyte. This can lead to the eventual death of the adipocyte as well as a characteristic inflammatory response. The inflammatory response includes increased production and release of proinflammatory cytokines/chemokines and the recruitment of bone marrow–derived macrophages (Mϕ). These macrophages are of the M1 activation/polarization state and are highly inflammatory in nature. Once recruited, these macrophages release proinflammatory cytokines, which work in a paracrine manner to activate the intracellular proinflammatory pathways (e.g., JNK and IKK) in neighboring cells and possibly through endocrine mechanisms in distal tissues. In a feed-forward cycle, activation of macrophages promotes the recruitment and infiltration of additional macrophages into adipose tissue. This results in cell autonomous insulin resistance in adipocytes and liver, exacerbation of the inflammatory state, and systemic insulin resistance. With obesity, there is also increased fat accumulation within skeletal muscle, and these intermuscular fat depots becomes infiltrated with proinflammatory macrophages, which may cause paracrine-like insulin resistance in skeletal muscle. In parallel with these inflammation-related changes, alterations in fatty acid metabolism can lead to the accumulation of fatty acid intermediates with the liver and skeletal muscle, which can cause insulin resistance via mechanisms outlined in Figure 1. In addition, fatty acids can serve as ligands to broadly activate inflammatory pathways in Kupffer cells and ATMs (e.g., via TLR2/TLR4 signaling pathways).