Cell cycle regulators in pancreatic development and disease
Several years ago, we generated mouse models that led to the revelation of the role of cell cycle machinery, specifically of Cdk4, in regulation of beta cell mass. These mouse models revealed a crucial role for Cdk4 and the cell cycle machinery in regulation of beta cell mass, and offered potential clinical applications for diabetes therapy. Mechanisms of islet growth and the pathways that lead to increases in beta cell mass are topics of active debate and are areas of active investigation. We hypothesize that cell cycle regulators play a critical role in development, growth, maintenance, and regeneration of the beta cell compartment, and we continue to explore further this area of research using mouse models, primary cell culture, and established cell lines.
Cell cycle regulators in obesity, diabetes, and associated complications
This project aims to understand the importance of cell cycle regulators in the growth, development, differentiation, and death of cells that comprise the organs tasked with maintaining normal glucose tolerance and glucose homeostasis. In addition, the goal is to determine how cell cycle molecules and the downstream pathways are deregulated during pathogenesis of obesity and diabetes. We will use mouse models that have mutations in the Cdk locus. Because Cdks are regulators of the E2F-RB pathway, we hypothesize that Cdk activity may regulate adipogenesis and muscle development and function. Further, the effect of Cdks on glucose homeostasis may impact the overall energy balance. We are studying mechanisms of glucose tolerance and energy homeostasis by evaluating Cdk-dependent functions in different metabolic organs. Initial findings are revealing the important role of Cdks in processes that modulate energy balance.
TGF-β superfamily signaling in diabetes and obesity
The transforming growth factor beta (TGF-beta) superfamily, which includes TGF-beta, activin, and BMP, has been implicated in pancreatic development and pancreatic diseases. BMP signaling appears to play a role during early pancreatic development and in regulating mature beta cell function, whereas activin signaling has been shown to play a role in islet morphogenesis and establishment of beta cell mass. Our recent observations are consistent with a complex role for TGF-beta signaling in regulation of beta cell function. Interestingly, TGF-beta levels are elevated in diabetes, diabetes-associated complications, and obesity. Using mouse models, primary cells, established cell lines, and human samples, we are actively studying the role of the TGF-beta superfamily in obesity and diabetes.
TGF-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta cell function
We defined an important role of the TGF-beta pathway in regulation of insulin gene transcription and beta cell function. We identified insulin as a TGF-beta target gene and showed that the TGF-beta signaling effecter, Smad3, occupies the insulin gene promoter and represses insulin gene transcription. Moreover, Smad3 deficiency resulted in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. These studies emphasize TGF-beta/Smad3 signaling as an important regulator of insulin gene transcription and beta cell function and suggest that components of the TGF-beta signaling pathway may be deregulated in diabetes.
Protection from obesity and diabetes by blockade of TGF-beta/Smad3 signaling
Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. We illustrated an important role of the TGF-beta/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3-deficient white adipose tissue, acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3-deficient adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1alpha expression. We observed a significant correlation between TGF-beta1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta signaling protected mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta activity might be an effective treatment strategy for obesity and diabetes.
We continue to examine the mechanistic underpinnings of the above-mentioned observations as they relate to the role of TGF-beta family signaling in diabetes and obesity pathogenesis.