Lifespan Data from Multiple Tissue-Specific GH Receptor Gene Disrupted Mouse Lines Indicate That Removal of GH Action in Adipose Tissue Is Detrimental to Aging, While Removal in Muscle or Liver Is Not
Presentation Number: OR40-3
Date of Presentation: April 4th, 2016
Edward Owen List*1, Darlene E Berryman1, Jesse Kowalski1, Celina Sarkes2, Mathew Buckman1, Austin Stevens2, Stephen Bell2, Conor Brockman2, Patrick Ruz2 and John J Kopchick1
1Ohio University, Athens, OH, 2Ohio University, athens, OH
While disruption to the growth hormone receptor (GHR) gene in humans produces Laron Syndrome (LS) with severe short stature, several extraordinary health benefits have been described including protection from diabetes and cancer. To help study this in laboratory mice, GHR gene disrupted mice (GHR-/-) have been generated and have several phenotypes in common with LS patients. However, determining the direct actions of GH on specific tissues in organisms with global GHR knockout is limited. Thus, our laboratory has generated a number of tissue-specific GH receptor gene disrupted mice in order to better understand how GH action in specific tissues contributes to physiology and long-term health. We have previously published that conditionally disrupting the GHR gene specifically in muscle (MuGHRKO mice) replicates some of the health benefits seen in global GHR-/- mice. Furthermore, removal of GHR specifically in liver (LiGHKO mice) did not alter lifespan despite impaired glucose homeostasis. This was surprising since most physiological signs pointed to a decreased lifespan. That is, LiGHRKO mice have elevated IL-6 and CRP, and develop fatty liver in addition to impaired glucose homeostasis. However, LiGHRKO mice have a 90% reduction in circulating IGF-1. Since reduced IGF-1 has been found to be a ‘common theme’ in slowing aging and promoting longevity, it appears that reduced IGF-1 compensates for multiple negative effectors of aging to preserve normal lifespan in LiGHRKO mice. In the current study, we analyzed longevity in fat-specific GHR gene disrupted (FaGHRKO) mice to determine the long-term impact when GH insensitivity is specifically limited to adipose tissue. Our data indicate that removal of GHR specifically in adipose tissue produces a significant decrease in lifespan despite normal measures of glucose homeostasis. For FaGHRKO mice, significantly increased adiposity may have contributed to decreased lifespan. However, since this increased adiposity was not associated with impairment to glucose homeostasis, this line of reasoning remains questionable. Taken together, data from all three mouse lines suggest that mechanisms other than those affecting glucose metabolism plays a more predominant role in controlling lifespan in LiGHRKO and FaGHRKO mice in contrast to MuGHRKO.
Nothing to Disclose: EOL, DEB, JK, CS, MB, AS, SB, CB, PR, JJK