Molecular Basis of Obesity and Type 2 Diabetes

The Lowell Lab is an Integrative Molecular Physiology group which utilizes genetic engineering techniques in mice to study peripheral and central pathways controlling energy metabolism.  Specific areas of investigation are briefly reviewed below.

 1)  Mechanisms of Diet-Induced Thermogenesis. bARs and the sympathetic nervous system are necessary for diet-induced thermogenesis and this pathway is critical in the defense against diet-induced obesity (Bachman et al., Science 297:  843-5, 2002). Using b-less mice as the genetic background, we are transgenically re-expressing bARs in candidate thermogenic target tissues and then assessing effects on diet-induced thermogenesis and diet-induced obesity.  This powerful, "genetic rescue" approach will lead to the identification of the target tissue mediating diet-induced thermogenesis.

 2) Uncoupling Protein (UCP)-Mediated Mitochondrial Proton Leak and its Role in the Pathogenesis of Type 2 Diabetes. UCP2 negatively regulates insulin secretion and upregulation of UCP2 in obesity causes pancreatic b-cell dysfunction (Zhang C, et al., Cell 105:  745-55, 2001).  Future studies are focused on identifying cellular factors which control UCP2 activity and the importance of these factors for the pathogenesis of type 2 diabetes. One such factor is superoxide, which stimulates UCP2-mediated proton leak.  Of interest, superoxide is a normal byproduct of mitochondrial electron transport chain function and its production is markedly increased in b–cells in type 2 diabetes.  Thus, diabetes is associated with increased UCP2 protein, as well as the level of it’s activator, superoxide.  This superoxide – UCP2 pathway contributes importantly to the development of beta cell dysfunction in type 2 diabetes (Krauss S., et al., J Clin Invest 112:  1831-42, 2003).  These findings are likely to have important implications for the cause and treatment of type 2 diabetes.

 3) Functional Neurocircuitry of Body Weight Control. Neuroanatomical mapping studies have identified neurocircuits which may be important in regulating food intake and energy expenditure.  We, in close collaboration with Joel Elmquist’s group, are using conditional, neuron-specific gene targeting methods to determine the functional importance of these neurocircuits in controlling body weight.  Techniques being utilized include BAC transgenesis, neuron-specific knockouts, neuron-specific gene reactivations and neuron-specific cell ablation.

 Balthasar N*, Coppari R*, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr.**, Elmquist JK** and Lowell BB**.  Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.  Neuron. 2004;42:983-91

                      * = equal contributing first authors, ** = joint senior authors.

 4)  Role of PGC-1 in controlling mitochondrial biogenesis and function. Gain of function studies, by Dr. Bruce Spiegelman’s group, have shown that PGC1a and PGC1b are transcriptional co-activators which can regulate mitochondrial biogenesis and function.  As part of a collaborative effort with Dr. Spiegelman’s group, we have generated PGC1a and PGC1b gene knockout mice.  These animals are being studied to gain insight into the role of these co-activators in controlling mitochondrial function in vivo.