NEWS AND VIEWS
The humoral side of insulin resistance Mitchell A Lazar
There is not much amusing about type 2 diabetes and cardiovascular disease, conditions that threaten individual lifespan in the industrialized world. Insulin resistance, most commonly in the context of obesity, is the major risk factor for these devastating diseases1. Not long ago, it seemed plausible that insulin resistance resulted from a defect inherent in the insulin signaling pathway, which is common to many insulinresponsive cell types. Indeed, there is only a single insulin receptor, and individuals who lack it or have antibodies against it develop severe insulin resistance 2 . However, postulating a cell-autonomous, intrinsic receptor defect does not explain the link between obesity and insulin resistance; indeed, as insulin is anabolic and enhances fat storage, insulin resistance in adipose tissue might be expected to mitigate obesity. An alternative theory postulates that insulin resistance arises when pathological levels of humoral factors disrupt insulin signaling in responsive tissues. This humoral theory emerged from the recently recognized role of adipose tissue as a secretory organ 3, and provided an obvious link between obesity and insulin resistance. Last year, Shoelson and colleagues elegantly confirmed and extended the humoral theory by demonstrating that an inflamed liver can also be the primary source of systemic factors that lead to the development of insulin resistance4. The role of the adipose tissue as a hormone-producing organ became clear in 1994 with the discovery of leptin as an adipocyte-secreted protein, the deficiency of which causes morbid obesity and diabetes5. But, the year before, Hotamisligil and Spiegelman prophetically described a relationship between adipose expression of the inflammatory cytokine tumor necrosis facThe author is in the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191046149, USA. E-mail:
[email protected]
Obesity
Inflammation
Adipocyte hypertrophy
Innate immune activation
Hepatic steatosis
Macrophages
DECREASED: Adiponectin
INCREASED: Resistin MCP-1
Artery
INCREASED: IL-6 TNF-α IL-1β
Muscle
Atherosclerosis
INCREASED: PAI-1 RBP4
Liver
Simon Fenwick
© 2006 Nature Publishing Group http://www.nature.com/naturemedicine
Primary alterations in insulin signaling pathways are not the only way to reduce the body’s sensitivity to insulin. By promoting the release of cytokines, liver inflammation can also lead to insulin resistance.
Insulin resistance
Figure 1 The humoral theory of insulin resistance. In this model, insulin resistance results from pathophysiological levels of circulating factors that are potentially derived from several different cell types. The possible role of adipocytes, macrophages (in adipose tissue, liver and elsewhere), and hepatocytes is shown, along with secreted factors that modulate insulin action at the cellular level.
tor (TNF)-α and obesity-associated insulin resistance6. It now seems that the adipose tissue secretes many factors—collectively termed ‘adipokines’—that include adiponectin, resistin, retinol binding protein 4 and numerous classical cytokines including interleukin (IL)-6 (ref. 7). In obesity, secretion of these factors is dysregulated in a way that is generally detrimental to insulin action on peripheral tissues. Some adipokines are involved in innate immunity and are also produced by macrophages. Remarkably, bone marrow–derived macrophages home to adipose tissue in obesity8,9. Increased secretion of resistin and cytokines by adipocytes and macrophages in adipose tissue, together with decreased adipocyte secretion of the insulin-sensitizing hormone adiponectin, all contribute to the bad humor of obesity by producing insulin resistance in muscle and liver (Fig. 1).
NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006
Another consequence of obesity is nonalcoholic fatty liver disease, which is a major cause of cirrhosis10. Increased intracellular lipids may induce hepatic insulin resistance by a nonhumoral mechanism11. However, the Shoelson group noted that obesity-associated hepatic steatosis is associated with increased activity of the NF-κB pathway in the liver4. Hypothesizing that this liver inflammation could have a causal role in systemic insulin resistance, they created liver-specific transgenic models of NF-κB activation or inhibition, and reported that increased NF-κB activity caused insulin resistance, whereas mice with reduced hepatic NF-κB activation were resistant to obesityinduced insulin resistance4. The insulin resistance caused by hepatic NF-κB activation was associated with increased expression of the genes that encode several cytokines, notably IL-6, TNF-α and IL-1β, and markedly
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© 2006 Nature Publishing Group http://www.nature.com/naturemedicine
NEWS AND VIEWS improved after antibody neutralization of circulating IL-6. These observations strongly support the idea that the inflamed liver can be the primary source of humoral factors that cause systemic insulin resistance (Fig. 1). A related paper published simultaneously by Karin, Olefsky and colleagues independently showed that a liver-specific impairment of NF-κB activation attenuates obesity-associated insulin resistance12. In this complementary model, insulin signaling was preserved in the liver but not in muscle, suggesting a paracrine, rather than endocrine, role of an NF-κB–dependent factor. Together, these studies show that the liver, in addition to adipose tissue, can be the primary source of factors that cause insulin resistance. Once initiated, it is likely
that these humoral mediators lead to secondary changes in target tissues that further promote insulin resistance. Such feedforward humoral mechanisms could also explain how tissue-specific signaling abnormalities cause insulin resistance throughout the body, including tissues without intrinsic defects13. Clearly, many paths lead to insulin resistance. A major challenge is now to determine whether effective treatment of insulin resistance and its complications requires reversal of the primary defect, such as obesity or inflammation, or whether blocking the actions of one or more humoral factors would be an alternative strategy. So, given the urgency and enormity of the problem, understanding the mechanism underlying obesity-associated insulin resistance
requires a better sense of humor(s) now more than ever. 1. Eckel, R.H., Grundy, S.M. & Zimmet, P.Z. Lancet 365, 1415–1428 (2005). 2. Kahn, C.R. et al. N. Engl. J. Med. 294, 739–745 (1976). 3. Kershaw, E.E. & Flier, J.S. J. Clin. Endocrinol. Metab. 89, 2548–2556 (2004). 4. Cai, D. et al. Nat. Med. 11, 183–190 (2005). 5. Zhang, Y. et al. Nature 372, 425–432 (1994). 6. Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Science 259, 87–91 (1993). 7. Berg, A.H. & Scherer, P.E. Circ. Res. 96, 939–949 (2005). 8. Weisberg, S.P. et al. J. Clin. Invest. 112, 1796–1808 (2003). 9. Xu, H. et al. J. Clin. Invest. 112, 1821–1830 (2003). 10. McCullough, A.J. Clin. Liver Dis. 8, 521–533, viii (2004). 11. Petersen, K.F. et al. Diabetes 54, 603–608 (2005). 12. Arkan, M.C. et al. Nat. Med. 11, 191–198 (2005). 13. Biddinger, S.B. & Kahn, C.R. Annu. Rev. Physiol. (doi:10.1146/annurev.physiol.68.040104.124723).
Improving metabolism by increasing energy expenditure Johan Auwerx A reduction in mitochondrial activity and the subsequent decrease in energy expenditure contribute substantially to metabolic dysfunction in aging, insulin resistance and diabetes. Enhancing mitochondrial activity could improve metabolic homeostasis. The onset of type 2 diabetes is almost always preceded by insulin resistance in skeletal muscle. Although insulin resistance is one of the best predictors for the development of diabetes, its causes remain largely elusive. Two studies by Petersen and colleagues1,2 linked defects in mitochondrial oxidative phosphorylation—the process by which the mitochondria synthesizes ATP—to insulin resistance in the skeletal muscle of elderly subjects and of healthy relatives of individuals with type 2 diabetes. Petersen et al. used sophisticated metabolic techniques on elderly and young subjects matched for lean and fat mass, and showed that the older subjects were markedly resistant to insulin, as determined by the reduced stimulation by insulin of muscle glucose metabolism1. These changes occurred in parallel with fat accumulation in liver and muscle and reduced oxidative phosphorylation. Remarkably, and unlike what is most commonly seen, the authors did not observe changes in mitochonThe author is at the Institut de Génétique et Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP) and at the Institut Clinique de la Souris, 67404 Illkirch, France. E-mail:
[email protected]
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drial energy coupling (as is seen when there is abnormal activity of the mitochondrial uncoupling proteins). This suggested an age-related reduction of mitochondrial number and/or function as the most likely culprit to explain reduced oxidative phosphorylation. Strikingly, the healthy, young, lean, insulin-resistant offspring of individuals with diabetes also displayed defective muscle oxidative phosphorylation and lipid metabolism2, as well as lower ratios of type I muscle fibers (which depend on oxidative phosphorylation to produce energy) relative to type II fibers (which depend on glycolysis and not on mitochondria). The fact that young family members of individuals with diabetes showed abnormal oxidative phosphorylation pointed to the possible existence of an inherited defect2, as opposed to the presumably acquired defect that develops in the elderly1. In this regard, a study that selected rats for their low or high intrinsic energy capacity (as reflected by their capacity to run on a treadmill) over 11 generations provided additional support for the genetic determination of mitochondrial activity3. In these rats, cardiovascular risk factors segregated with low aerobic capacity and reduced expression of genes required for the production of
mitochondria and oxidative phosphorylation in muscle. Further support for the importance of oxidative phosphorylation came from two studies in humans, showing decreased expression of genes that control mitochondrial activity in the muscle of individuals with type 2 diabetes and of their healthy first-degree relatives4,5. As transcriptional regulatory circuits maintain metabolic homeostasis to a large extent, metabolism is a sensitive indicator of the efficiency of these transcriptional mechanisms. It was therefore no surprise that, in these people, decreased aerobic capacity correlated with reduced expression of transcription factors and co-regulators required for mitochondrial function. A case in point is the peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC-1α), which controls adaptive thermogenesis—the regulated production of heat by burning calories—in adipose tissue and skeletal muscle by stimulating the generation of mitochondria and oxidative phosphorylation6,7. Expression of PGC-1α is finely tuned in these tissues to reflect cellular energy needs. For example, conditions of increased energy demands (such as cold, exercise or fasting) induce its expression. So, the healthy relatives of people with insulin
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