Obesity without insulin resistance: altered fatty acid metabolism in the liver associated with protection from insulin resistance

October 17, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Japan: New research provides more evidence that obesity and insulin resistance can be genetically separated. Scientists in Japan have made mice deficient in Elovl6, a member of the elongator of long-chain fatty acids family of enzymes that catalyze the conversion of palmitate (16:0) to stearate (18:0). Elovl6-deficient mice become obese when fed a diet high in fat and sucrose, however they have normal levels of insulin and normal insulin sensitivity. This research furthers our understanding of the connections between obesity, insulin sensitivity, and fatty acid metabolism.

Fatty acid synthesis occurs though a series of recurring reactions in the cytosol, each adding two carbons to the growing fatty acid chain. After the fatty acid is sixteen carbons in length, it is transported into the endoplasmic reticulum. The Elovl family of enzymes are membrane-bound enzymes in the ER that can complete the chain lengthening, creating the 18-carbon fatty acid stearate. A previous microarray analysis had suggested that the Elovl6 family member might be important for regulating fatty acid composition of tissues.

Mice deficient in Elovl6 demonstrated the expected perturbations in fatty acid content in the liver, having higher levels of 16-carbon fatty acids and lower levels of 18-carbon fatty acids. Interestingly, these fatty acid changes were not seen in muscle or fat tissues. The mice weighed slightly less than their wild-type littermates, but gained a similar amount of weight when fed a diet high in fat and sucrose. Despite their obesity, Elovl6-deficient mice had lower levels of insulin, had normal responses to administered insulin, and lacked the islet cell hyperplasia seen in obese wild-type animals. In response to a glucose challenge, the obese knockout mice had elevated plasma levels of glucose, just like obese wild-type mice. Their insulin response, however, was much less exaggerated, which correlated with preserved tissue responsiveness to lower levels of insulin.

The molecular basis for the disconnect between adiposity and insulin resistance in Elovl6-deficient mice is not entirely clear at present. Certainly the explanation is more complex than depletion of liver stearate, as diets enriched with stearate could not produce insulin resistance in Elovl6-deficient mice. With any knock-out experiment there is always the chance that global changes in gene expression unrelated to the enzymatic function of the targeted protein could explain the phenotype. The authors excluded this possibility by reproducing their finding using RNAi technology, and by inducing insulin-resistance in over-expression experiments. The authors have begun experiments to determine the molecular mechanism of preserved insulin resistance in Elovl6-deficient mice, and no doubt future work will provide more answers. Their findings raise the possibility that future therapeutics might target insulin resistance specifically, without affecting adiposity.


 * 1) ref1 pmid=17906635