Yuxiang Sun, M.D., Ph.D.
Children’s Nutrition Research Center, Huffington Center on Aging, Departments of Pediatrics and Molecular and Cellular Biology
Ph.D.: University of Manitoba, Winnipeg, Manitoba, Canada
Postdoctoral training: Huffington Center on Aging, Baylor College of Medicine, Houston
The Role of Ghrelin Signaling in Pathogenesis of Obesity and Diabetes
The incidence of obesity and diabetes has reached epidemic proportions worldwide, in all age groups. The primary cause of diabetes is obesity, which often leads to insulin resistance. Insulin resistance eventually causes pancreatic beta-cell failure, resulting in diabetes.
Ghrelin is the only circulating orexigenic hormone known to increase growth hormone (GH) release, stimulate appetite and promote obesity. To study the physiological functions of ghrelin signaling, we generated knockout mice for ghrelin and ghrelin receptor (aka, growth hormone secretagogue receptor, GHS-R). We discovered that ghrelin’s effects on GH release and appetite are directly mediated through GHS-R. Ghrelin signaling plays a major role in the etiology of diabetes. Ablation of ghrelin improves pancreatic beta-cell function, rescuing the diabetic phenotype of leptin-deficient ob/ob mice. Conversely, ablation of GHS-R prevents age-associated insulin resistance. Thus, targeting the ghrelin-signaling pathway may represent a novel strategy for treatment of pancreatic beta-cell impairment in diabetes.
Obesity is centered in adipose tissues, which consist of white adipose tissue (WAT) and brown adipose tissue (BAT). While white adipose tissues stores energy, BAT burns energy to generate heat (thermogenesis). BAT has recently been shown to be also present in adult humans; intriguingly, the thermogenic capacity of BAT is decreased in obese subjects and the elderly. Our recent findings indicate that GHS-R expression in BAT increases with age. Consequently, ablation of GHS-R increases BAT thermogenesis during aging, leading to a lean, insulin-sensitive and youthful phenotype, without changes in either food intake or physical activity. Thus, blockade of the ghrelin receptor may offer a novel approach for weight loss – “burning energy by producing heat, without dieting or excise”.
Our short-term goals are to study the functions of the ghrelin-signaling pathway in energy and glucose homeostasis under specific nutritional and metabolic conditions: 1) to investigate the roles of ghrelin-signaling in pancreatic islet biology by studying insulin secretion and counter-regulation; 2) to elucidate the roles of ghrelin-signaling in insulin resistance by studying central glucose sensing in the hypothalamus, and peripheral insulin sensitivity in liver, muscle and fat; 3) to further elucidate the cellular and molecular mechanisms by which ghrelin and its receptor promote obesity and diabetes. Physiological and pharmacological approaches will be carried out in global and tissue-specific knockout and knockin mice, as well as in primary cells and tissue culture systems.
Our long-term goal is to understand the pathophysiology of obesity and diabetes, and to identify the key regulatory genes and regulatory signaling pathways involved in the pathogenesis of obesity and diabetes. Insulin sensitivity is a hallmark of healthy aging; healthspan and lifespan are tightly related to insulin sensitivity. We hope to develop novel therapeutic approaches to combat obesity and diabetes, ultimately improving healthspan and lifespan of humans.
Baylor College of Medicine
One Baylor Plaza MS: BCM320
1100 Bates St., Room 5024
Houston, TX 77030
- Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, Buras ED, Tong Q, Chan L, McGuinness OP, Sun Y * (2011) Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell 10:996-1010.
- Ma X, Lin L, Qin G, Lu X, Fiorotto M, Dixit VD, Sun Y. (2011). Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging. PLoS ONE 6:e16391.
- Delhanty P, Sun Y, Visser j, Kerkwijk A, Huisman M, IJcken W, Swagemakers S, Smith RG, Themmen AP, Lely AJ. (2010). Unacylated Ghrelin Rapidly Modulates Lipogenic and Insulin Signaling Pathway Gene Expression in Metabolically Active Tissues of GHSR Deleted Mice. PloS ONE 5: e11749.
- Kohjima M, Sun Y, Chan L.(2010). Increased food intake leads to obesity and insulin resistance in the Tg2576 Alzheimer's disease mouse model. Endocrinology 151:1532-1540.
- Szentirmai E, Kapás L, Sun Y, Smith RG, Krueger JM. (2009). The preproghrelin gene is required for the normal integration of thermoregulation and sleep in mice. Proc Natl Acad Sci U S A. 106: 14069-14074.
- Sun Y, Butte NF, Garcia JM and Smith RG. (2008). Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology 149:843-850.
- Sun Y, Asnicar M and Smith RG. (2007). Central and peripheral roles of ghrelin on glucose homeostasis. Neuro-endocrinology 86:215-228.
- Dixit VD, Yang H, Sun Y, Weeraratna AT, Youm YH, Smith RG and Taub DD. (2007). Ghrelin promotes thymopoiesis during aging. Journal of Clinical Investigation 117:2778-2790.
- Sun Y, Garcia JM and Smith RG. (2007). Ghrelin and growth hormone secretagogue receptor expression in mice during aging. Endocrinology 148:1323-1329.
- Sun Y, Asnicar M, Saha PK, Chan L and Smith RG. (2006). Ablation of Ghrelin Gene Improves the Diabetic but not Obese Phenotype of ob/ob Mice. Cell Metabolism 3:379-386.