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Department of Human Health and Nutritional Sciences University of Guelph Guelph, Ontario, Canada N1G 2W1
Address all correspondence and requests for reprints to: Dr. David J. Dyck, Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1. E-mail: ddyck{at}uoguelph.ca.
There is a clear association between obesity and the development of insulin resistance; however, the mechanisms underlying this relationship are unclear. In both humans and rodents, there is a strong correlation between abnormal fatty acid (FA) metabolism and the development of insulin resistance in skeletal muscle, the largest tissue by mass regulated by insulin. In addition to being a major sink for circulating glucose, skeletal muscle takes up significant quantities of plasma FA, for either energy production or storage. The accumulation of im triacylglycerol (TAG) (1, 2) as well as an impaired capacity to oxidize FA (3) are correlated to the presence of insulin resistance. However, elevated TAG stores may only be a marker of dysfunctional FA metabolism, and accumulation of more reactive lipid species, such as diacylglycerol (DAG) and ceramide, is likely to be responsible for the impaired insulin signaling. Interestingly, and perhaps somewhat surprisingly, the elevation of circulating lipids need not be present chronically to induce insulin resistance. Infusion of a lipid emulsion for several hours in humans results in increases in muscle DAG content (4) and the acute development of insulin resistance (5, 6).
If lipid overload in tissues such as skeletal muscle, which results in impaired insulin signaling, is due to an imbalance between FA uptake and oxidation, then it is logical to hypothesize that paradigms/treatments that increase FA oxidation should lower muscle lipid levels and lead to improved insulin sensitivity. This certainly appears to be the case with aerobic training in humans as well as the administration of hormones, such as leptin, in obese diabetic rodents (6). Since its discovery over 10 yr ago, the adipocyte-derived cytokine leptin has been studied extensively for its role as an antiobesity agent. Unfortunately, clinical studies examining the effectiveness of exogenous leptin administration as a means to facilitate weight loss in humans have proven disappointing. This is probably due to the development of leptin resistance, whether it be impaired movement of leptin across the blood-brain barrier or reduced responsiveness in peripheral tissues such as muscle (7) and liver (8). Ciliary neurotropic factor (CNTF), a member of the glycoprotein 130 receptor cytokine family, has been identified as a potential antiobesity agent in both humans and rodents. The receptor for CNTF is similar in homology to that of the long form of the leptin receptor and also activates the Janus kinase/signal transducer and activator of transcription pathway. Of considerable interest is the fact that CNTF can activate hypothalamic leptin pathways in obese rodent models resistant to leptin (9). This raises the intriguing prospect that CNTF may succeed as an antiobesity agent in cases where leptin does not. Indeed, CNTF has been demonstrated to correct obesity and diabetes associated with leptin deficiency in the ob/ob mouse (10).
In this issue of Endocrinology, Watt et al. (11) examine the ability of CNTF to prevent the acute Intralipid-induced development of insulin resistance in rodents as well as to measure changes in muscle lipid content and insulin signaling transduction. Importantly, this is the first study to examine the effects of CNTF on skeletal muscle metabolism. Although previous studies have generally elevated circulating lipids for a 3- to 5-h period to induce insulin resistance, Watt et al. demonstrate that insulin resistance can be induced in as little as 2 h. This may be due in part to the suparphysiological levels of circulating FA (2.5 mM) that Watt et al. achieve with their lipid infusion protocol. Whole-body insulin sensitivity was determined after the 2-h Intralipid infusion by the hyperinsulinemic, euglycemic clamp, in which the rate of glucose infusion is adjusted to maintain a constant, euglycemic state in the presence of hyperinsulinemia. The greater the sensitivity to insulin, the greater the required rate of glucose infusion. By including radiolabeled glucose (tracer) in the infusate, the investigators could also estimate hepatic glucose production. The ability of insulin to stimulate glucose disposal and suppress hepatic glucose production was impaired after lipid infusion, as expected. However, including CNTF during the 2 h of lipid infusion prevented both these impairments from occurring.
To determine whether the change in insulin sensitivity was due to altered muscle lipid metabolism, Watt et al. also assessed total TAG, DAG, and ceramide contents before and after lipid infusion (with and without CNTF) in oxidative soleus muscle. The soleus muscle is commonly used when assessing lipid metabolism and its regulation in skeletal muscle due to its high oxidative capacity and ability to use FA. Oxidative rodent muscle is also more sensitive to insulin than glycolytic muscle, making it a good choice to assess metabolic events in this study. Predictably, all three lipid pools increased as a consequence of lipid infusion, but only the increases in the TAG and ceramide pools were prevented in the presence of CNTF. Considering that TAG accumulation is unlikely to be the direct cause of impaired insulin sensitivity, these data imply that the accumulation of ceramide is of greater importance in influencing insulin signaling than the DAG pool. Consistent with this is the researchers’ finding that MLK3, a member of the MAPK kinase kinase family that is activated by ceramide, was also activated after lipid infusion, but not when CNTF was present. This is a noteworthy point, because both DAG and ceramide are potential candidates for interfering with insulin signaling. There is currently no agreement on which of these lipid species might be more important in the reduced insulin sensitivity commonly observed in obesity; thus, the data from the current report make an important contribution to this area of study. Importantly, the researchers also measured the phosphorylation of various components of insulin signal transduction from insulin receptor substrate-1 through Akt, demonstrating impairment with lipid infusion and restoration with CNTF. Although the mechanism by which CNTF prevents the accumulation of muscle lipids associated with impaired insulin signaling is not clear, Watt et al. include a very important subset of experiments in which they demonstrate that CNTF can acutely stimulate FA oxidation in isolated L6 myotubes. Thus, as with leptin, the lipid-lowering effect of CNTF is probably due in part to its ability to stimulate FA oxidation, thereby partitioning FA away from storage.
Although a major focus of the study by Watt et al. was to examine the acute effect of CNTF on muscle lipid metabolism and insulin signaling, the researchers also include metabolic measurements in the liver. This is a particularly nice feature of the present study, because it properly examines the contributions of both muscle (the major glucose sink) as well as liver (the major glucose producer) to the development of whole-body insulin resistance. Thus, another major contribution from this study is the demonstration that CNTF also acutely improves hepatic insulin sensitivity, which is associated with partial reversal of lipid-reduced insulin receptor substrate-1- and -2-associated phosphatidylinositol 3-kinase activity as well as the complete blockage of lipid-induced c-Jun N-terminal kinase activation.
The bottom line is that CNTF appears to be effective in preventing acute, lipid-induced insulin resistance in both skeletal muscle and liver. This appears to be due at least in part to a leptin-like effect, i.e. stimulation of FA oxidation and lowering of muscle lipids. Subsequent research examining the role of CNTF as a potential therapeutic agent for insulin resistance, particularly under more chronic conditions in obese models, will be very important.
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Abbreviations: CNTF, Ciliary neurotropic factor; DAG, diacylglycerol; FA, fatty acid; TAG, triacylglycerol.
Received January 27, 2006.
Accepted for publication February 2, 2006.
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in skeletal muscle of diabetic patients. Metabolism 50:553–557[CrossRef][Medline]
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