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Monday, October 4, 2010

Insulin Resistance and Inflammation

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

This is yet another paper demonstrating that the evidence strongly points to the fat cells being the origin of the sequences of events leading to peripheral insulin resistance.  This paper looked at inflammation.

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.

This group used several models of obesity in mice -- both genetic and diet induced.  Yes, it's a mouse study with all the inherent problems in applying results to humans.  The results:

Expression levels of genes in inflammatory pathways are significantly upregulated in WAT of obese mice. To study obesity and obesity-induced insulin resistance, we performed global transcriptional profiling studies with various tissues (WAT {note:  WAT = white adipose tissue}, brown adipose tissue, muscle, liver, stomach, hypothalamus, small intestine, and pancreas) taken from genetically obese mice, including ob/ob,db/db, tubby, agouti, and DIO {note: DIO = diet induced obesity} mice. Notably, we found that many of the most significantly upregulated genes in WAT were not known to be involved in adipocyte biology; instead, they could be broadly categorized as macrophage- or inflammation-related genes. Of the genes upregulated more than twofold in at least four of these five models, 59% (50/85) could be counted as inflammation genes, as determined by their known functions. The remaining genes were involved in diverse molecular pathways, including fat storage, cholesterol metabolism, DNA modification, transcription, cell division, signal transduction, and unknown functions  
In plain English, almost 3 out of 5 genes that were expressed in greater amounts in WAT are not associated with fat metabolism, but rather can be considered inflammation genes.
... with multiple models of genetic and diet-induced obesity, our data suggest that the inflammatory response is a general phenomenon of the obese state, independent of the availability of the leptin protein. We also noticed that this phenomenon was WAT-specific and was not observed in any other tissues we profiled. 
Inflammation is associated with the state of WAT adiposity irrespective of the various metabolic paths altered in the genetically obese mice or if adiposity was induced through diet.   The discussion does go on to mention that the same genes are not upregulated the same amount comparing various models, but there is consistency in the genes that are upregulated to some extent.
To determine whether the upregulation of these genes occurs prior to the development of systematic insulin resistance, which is characterized by hyperinsulinemia, we tracked the expression levels of these genes in WAT of mice with high-fat diet–induced obesity at multiple time points for 26 weeks. The body weight increased steadily over this period, as did the fasting blood glucose level, although the latter remained within the normal range (<120 mg/dl) until sometime after 16 weeks (Figure 2a). Meanwhile, we observed an increase in expression of some of these inflammation genes as early as 3 weeks on high-fat diet (Figure2b). Around 16 weeks on high-fat diet, a much more dramatic upregulation of these transcripts occurred, which correlated closely with a marked increase in fasting blood insulin levels (Figure 2). It appears that the adipose inflammatory response increases with an increase of adiposity, prior to the increase of fasting insulin level, but intensifies at the onset of hyperinsulinemia.
Lower level inflammation (dysfunction?) in WAT preceded an acute inflammation which seems to trigger insulin resistance (measured by fasting insulin).  This may have a snowball effect as hyperinsulinemia associated with IR may trigger more inflammation may trigger greater IR and so on and so on.  Other tissues (skeletal muscle, liver, spleen, lung) were studied and the inflammation genes were not significantly upregulated compared to lean controls except for the DIO after lengthy exposure (26 weeks) although the effect was still smaller than that seen in WAT.  It seems to me that this liver inflammation doesn't occur until the fat inflammation and IR has long since been established.  

Other conclusions of the study:

  • Inflammation is associated with macrophages in WAT that increase in the obese state.
  • Macrophage infiltration is a likely explanation for increased macrophages in the WAT of the obese.
  • Macrophage accumulation in WAT is highly correlated and perhaps causative of IR.
  • Macrophage activities increase after a certain degree of adiposity is achieved but before the onset of insulin resistance.
  • Obesity induced insulin resistance begins in WAT but spreads systemically as adiposity increases further.
The last quotation I'll C&P follows:
Macrophage accumulation is likely a direct response to the abnormal fat metabolism caused by the increasing adiposity. The molecular signals that trigger the macrophage activity in obese WAT are not yet known, but several good candidates exist. Adipocytes are known to secrete hormones, cytokines, and FFAs, most of which have been shown to play some role in inflammation and systemic insulin resistance.

The discussion goes on to discuss these various factors, etc.  It's not too bad a read for those interested.

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