The innate immune system provides organisms with rapid and well-coordinated protection from foreign pathogens. However, under certain conditions of metabolic dysfunction, components of the innate immune system may be activated in the absence of external pathogens, leading to pathologic consequences. Indeed, there appears to be an intimate relationship between metabolic diseases and immune dysfunction; for example, macrophages are prime players in the initiation of a chronic inflammatory state in obesity which leads to insulin resistance. In response to increases in free fatty acid release from obese adipose depots, M1-polarized macrophages infiltrate adipose tissues. These M1 macrophages trigger inflammatory signaling and stress responses within cells that signal through JNK or IKKβ pathways, leading to insulin resistance. If overnutrition persists, mechanisms that counteract inflammation (such as M2 macrophages and PPAR signaling) are suppressed, and the inflammation becomes chronic. Although macrophages are a principal constituent of obese adipose tissue inflammation, other components of the immune system such as lymphocytes and mast cells also contribute to the inflammatory cascade. Thus it is not merely an increased mass of adipose tissue that directly leads to attenuation of insulin action, but rather adipose tissue inflammation activated by the immune system in obese individuals that leads to insulin resistance. 1. Introduction The obesity epidemic in the USA continues to expand at an alarming rate, with a 75% increase in prevalence since 1980 [1]. The Centers for Disease Control and Prevention (CDC) reports that more than one-third of USA adults and over one-sixth of children and adolescents are obese. The frequencies of other metabolic disorders have increased pari passu, including dyslipidemia, nonalcoholic steatohepatitis, and type 2 diabetes. Dysfunctional adipose tissue is central to all these conditions. Adipose tissue is increasingly recognized as a complex endocrine organ and not merely a depot for storage of fat. Adipose tissue in obese persons develops an inflammatory milieu which ultimately leads to insulin resistance. Although many components of the immune system have been found to play a role in either promoting or attenuating adipose tissue inflammation, macrophages are key players. This paper discusses the various stimuli and networks that lead to insulin resistance, with a primary focus on the role of macrophages in adipose tissue inflammation. 2. Macrophage Accumulation in Visceral Adipose Tissue in Obesity Adipose tissue
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