Core Message
The data available on GHR−/− at all ages. Glucose levels, which are very low in young animals, seem to normalize at older ages. Insulin levels remain significantly lower than normal throughout the lifespan of GHR−/− mice. Together, these data suggest that insulin sensitivity decreases only slightly as GHR−/− mice age. In addition, circulating lipid levels tend to be decreased, adding to the scenario of improved metabolic health in GHR−/− mice. However, the need for closer inspection of the age-dependent changes in metabolism in these mice is apparent. Given the age-dependent variation observed in blood glucose levels, it becomes critical to establish the insulin responsiveness of target organs in GHR−/− mice of different ages. Interestingly, data available on liver suggest an insulin-resistant state in older animals. This seems counterintuitive given that whole-body insulin sensitivity is enhanced in GHR−/− mice even at old age. Therefore, it would be interesting to evaluate the insulin responsiveness of the liver in young GHR−/− animals to determine the role of this organ in whole-body insulin sensitivity. Similarly, a thorough characterization of the age-specific degree of insulin sensitivity in skeletal muscle and heart is needed to complement the data that are already available. Furthermore, focus needs to be applied on adipose tissue, given that it is one of the main target organs of insulin and GH action and a key player in metabolic regulation (see Chap. 51).
However, insulin sensitivity is the result of complex metabolic regulation. Other factors, such as PPAR isoforms, mainly PPARγ, can also affect insulin responsiveness. In the liver, contrary to the low activation status of insulin signaling intermediates, PPARγ expression is high. Increased activity of this insulin-sensitizing molecule might compensate the apparent inactivity of the insulin signaling cascade, leading to the overall inhibition of glucose production. High PPARα levels leading to increased fatty acid oxidation may contribute to the insulin responsiveness by decreasing lipid levels in the blood. However, the action of PPAR isoforms in tissues such as liver, muscle, and heart is still not clear, and further research is necessary to establish the influence that these molecules have on metabolic regulation.
Interestingly, GHR−/− mice are not resistant to weight gain induced by a high-fat diet, but their glucose and insulin levels remain significantly lower than controls even after the weight gain. On the other hand, soy-derived diets affect lipid and glucose levels differently, with a genotype-specific increase in cholesterol and glucose tolerance only in the high isoflavone diet.
The beneficial effects on insulin sensitivity, in spite of obesity observed in GHR−/− mice, raise interesting questions about the relationship between GH, insulin signaling, and metabolism. These topics are of major concern in today’s world, given the widespread prevalence of obesity, insulin resistance and diabetes. However, the current information is far from enough to answer all the questions. Further research is needed to shed light on the complex mechanisms of metabolic regulation.
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Sackmann-Sala, L., Miles, D.R.B., Kopchick, J.J. (2011). Metabolism and Metabolic Regulation. In: Laron, Z., Kopchick, J. (eds) Laron Syndrome - From Man to Mouse. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-11183-9_52
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