In this Perspective, we first discussed possible factors that acutely (i.e., hours to days) modulate insulin sensitivity, independently of significant weight gain or weight loss. This centered primarily on nutrient “sensors” within skeletal muscle and liver and their interactions with the insulin-signaling cascade. These sensors can detect perturbations in nutrient availability and, depending on the nutrient status of the cell, regulate insulin action and nutrient (i.e., glucose) uptake. These processes provide a means of regulating insulin sensitivity that is cell autonomous (i.e., intrinsic to the cell) and independent of extracellular stimuli. Most likely these effects are distinct from the mechanisms of chronic inflammation– and obesity-induced insulin resistance, summarized below.
Potential mechanisms of chronic insulin resistance in obesity are summarized in Figure . This long-term regulation of insulin sensitivity is primarily related to expansion of adipose tissue mass, which leads to increased systemic fatty acid flux, microhypoxia in adipose tissue, induction of ER stress, and ultimately, adipose tissue inflammation. In relation to fatty acid flux and metabolism, as summarized in Figure (and integrated into Figure ), in obesity, the capacity of myocytes and hepatocytes to fully metabolize fatty acids is generally insufficient to match the excessive fatty acid uptake by cells. This can lead to the cellular accumulation of fatty acid intermediates (e.g., DAG, ceramide, acylcarnitines), which ultimately results in activation of a number of serine kinases, including JNK1, IKKβ, and PKC-θ. The activation of these serine kinases is significant because these kinases represent a convergence point central to inflammation-induced insulin resistance.
In parallel with the perturbations in fatty acid metabolism in skeletal muscle and the liver, adipocyte microhypoxia and ER stress precipitate a series of events that result in the recruitment of a specific population of proinflammatory, M1-like macrophages into adipose tissue. The characteristic properties of these macrophages are presented in Table . Activation of these macrophages leads to the release of a variety of chemokines (which recruit additional macrophages) and proinflammatory cytokines. In turn, these cytokines initiate a paracrine process that causes activation of proinflammatory pathways within nearby insulin target cells, such as adipocytes and hepatocytes, leading to cell autonomous insulin resistance in these cells. In the adipocyte, this exacerbates lipolysis, while in the hepatocyte, hepatic glucose production is increased. Thus, this cycle provides a mechanism for the inflammation-related component of insulin resistance in liver and adipose tissue.
Characteristic properties of macrophages in adipose tissue in the lean or obese state
The mechanisms by which inflammatory processes contribute to skeletal muscle insulin resistance are less clear. One likely contributory factor is that the macrophage-mediated inflammatory process within adipose tissue and liver changes the milieu of secreted circulating adipokines and/or cytokines, which then have endocrine effects to reduce insulin sensitivity in skeletal muscle. The possibility also remains that inflamed adipose and/or liver tissue releases heretofore-unidentified metabolites or novel peptides that have effects on insulin sensitivity in skeletal muscle. These possible endocrine effects could be exacerbated by the fact that inflammatory cytokines, such as TNF-α, stimulate adipocyte lipolysis, thereby enhancing fatty acid flux (14
). The skeletal muscle is also interspersed with adipose tissue, and this depot is increased in obesity and is a strong predictor of insulin resistance (125
). Moreover, this intermuscular adipose depot is infiltrated with approximately 3 times more macrophages in skeletal muscle from obese compared with lean mice (101
). Similar to the paracrine effects of macrophages in adipose tissue and liver, these macrophages could produce localized proinflammatory cytokines that affect skeletal muscle insulin sensitivity. Altogether, these possibilities suggest that the expanding adipose tissue mass is the primary cause of systemic insulin resistance in obesity and that the disordered homeostasis, inflammation, and insulin resistance that occur in adipose tissue communicate with skeletal muscle, causing skeletal muscle insulin resistance.
From a more general perspective, chronic tissue inflammatory responses (and macrophage recruitment) serve a normal physiologic purpose, such as host defense, tissue repair, or adaptive restoration of tissue homeostasis in response to cellular stress. Often, however, tissue inflammation becomes chronic or remains unresolved and progresses to a pathophysiologic condition. For example, in other disease states, such as cancer and Alzheimer disease, this may involve fibrosis, metaplasia, and/or destructive tissue damage. In obesity, the pathophysiologic consequence of chronic adipose tissue inflammation is a shift in the homeostatic set point, resulting in insulin resistance and disordered glucose homeostasis.
In conclusion, both acute and chronic insulin resistance have complex etiologies, and the components of insulin resistance are unlikely to be the same in all individuals and groups. We have tried to assemble the current knowledge in these wide-ranging areas and have considered these inputs from an integrative physiologic perspective. Clearly there are multiple mechanisms that can have an impact on insulin action, both in the initial stages of positive energy balance (i.e., before weight gain) and during obesity. These center around a complex interplay among nutrient availability, fatty acid metabolism, adipose tissue hypertrophy, and inflammatory pathways. Furthermore, as mentioned at the outset of this Perspective, there are other influences on insulin sensitivity, such as genetics and CNS effects, that have not been discussed in this review. This reinforces the concept that systemic in vivo insulin resistance is not a molecular diagnosis but rather a final general manifestation reflecting the interaction of multiple organ systems and a variety of overlapping but mechanistically distinct signaling and metabolic pathways. While the importance of insulin resistance has been recognized for many years, much work still remains in order to unravel all of its intricacies.