Associate Investigator, Edison Biotechnology Institute
Undergraduate Students: Stephen Bell, Austin Stevens, Patrick Ruz, Gabrielle Tharp, Nick Madama-Baumgaertel, Jordyn Sigerman, Joshua Bailey, Savannah McKenna, Abigail Faires & Julie Slyby
Growth Hormone, Obesity, Weight Loss, Diabetes and Aging
The main focus of my research has centered on GH and dissecting out the various actions of this pleotropic hormone in various tissues. Perhaps the most important of these actions I have studied (which represent the majority of my research interests) involve the health benefits that occur as a result of blocking GH action. GH receptor (GHR) gene knockout mice (GHRKO) have greatly enhanced insulin sensitivity, are resistant to diabetes, age related increases in cellular senescence and cancer, and are extremely long-lived. In attempts to further dissect the role of GH action on individual tissues and to understand how blocking GH action contributes to the health benefits observed in GHRKO mice at the tissue level, we had generated tissue-specific GHRKO mice. Results of our work with liver-specific GHRKO mice has helped to establish that: liver derived IGF-1 which make up the majority of circulating IGF-1 is indeed important for normal body growth (this has historically been a controversial topic); liver-specific GHR gene disruption results in increased IGF-1 expression in several extra-hepatic tissues, which results in a body composition profile similar to GH transgenic mice (increased body fat at early ages with decreased body fat at later ages); GH indirectly regulates adiponectin production from adipose tissue by acting directly on liver. These studies have provided important information with regards to how and where reductions in GH action can produce healthy aging. Adipose-specific GHRKO mice are of particular interest because they are obese but appear otherwise healthy with normal glucose metabolism. This research is important because it indicates that removal of GH action on adipose tissue results in “healthy” obesity. Results from muscle-specific GHRKO mice have recently been accepted by the journal “Aging”. Importantly, these mice replicate some of the health benefits found in global GHRKO mice. Collectively, these studies have provided important information on how tissue-specific reductions in GH action can produce healthy aging.
Another of my ongoing studies takes advantage of GH’s lipolytic and anti-lipogenic activities to explore the effects of GH in mouse models of obesity and type 2 diabetes. These studies have shown that GH treatment can improve body composition and reverse many aspects of type 2 diabetes. Furthermore, we were the first to demonstrate that GH therapy can reverse fatty liver. Unfortunately one of the negative consequences of GH is that it is diabetogenic and possesses anti-insulin activity. Thus, we are now studying an experimental variant of GH that lacks the anti-insulin activity of normal GH and exploring its use as a therapeutic agent for treating obesity and fatty liver disease.
Lastly, I also have an interest in studying the effects of weight cycling (also called yoyo-dieting) on long term heath. Results of our studies suggest that life-long weight cycling is healthier than remaining obesity and that weight loss itself can reduce the number of senescent cells present in adipose tissue. Senescent cells accumulate in most tissues over time and are thought release inflammatory cytokines which contribute to the progression of many age related diseases resulting in accelerated aging. Thus, reduction the number of senescent cells should delay disease and slow the aging process. Translation of this work is important since it suggests that individuals that are overweight or obese should not give up trying to lose weight based on fears that repeated failed attempts and subsequent weight cycling is more harmful than remaining obese. More importantly, our findings suggest that a previously undescribed benefit to weight loss may be a reduction of cellular senescence in WAT.