Obesity and its associated comorbidies such as type 2 diabetes mellitus, impose a significant burden on patients, society, and the economy. So far development of pharmacological interventions that can effectively induce sustained weight loss has been hindered, mainly by the lack of knowledge about the precise path physiological mechanisms leading to obesity. As a result, weight loss operations, particularly Roux-en-Y gastric bypass (RYGB) surgery, remain the only definitive treatment available to morbidly obese patients. RYGB significantly alters body weight and energy balance. Therefore, it represents a unique experimental model for the scientific investigations on the underlying mechanisms involved in metabolic deregulation and obesity. Adipose tissue plays a central role in the regulation of energy expenditure and its dysfunction has been shown to lead to obesity. In this application, we propose to study the effects of RYGB on adipose tissue function, phenotype, and metabolic rate. The central hypothesis to be tested in this proposal is that the profound physiological effects of RYGB are partially mediated by induction and activation of brown adiposities within both white and brown adipose tissues (WAT and BAT, respectively). The overall objective of this application is to determine the degree to which WAT and BAT contribute to the increase in metabolic rate, and ultimately weight loss, after RYGB.
The specific aim 1 is to assess the extent of the metabolic and phenotypic remodeling of each fat type after RYGB. First, the changes in the population of brown adiposities in several WAT and BAT depots will be determined over a period of three months after surgery. Genomic, proteomic, and morph metric techniques will be employed. Second, the RYGB-induced alterations in the metabolic rate of the adipose tissue will be elucidated by measuring respiration rate in ex vivo tissue explants cultures.
The specific aim 2 is also composed of two sub aims. First, the origin of the brown fat cells that appear in WAT proceeding RYGB will be identified. The approach is to label the proliferating pre-adiposities with BrdU and determine if the label propagates into the novel brown fat cells. Secondly, the key genes and molecular pathways involved in WAT and BAT remodeling will be identified through genome-wide expression. Lastly, in the specific aim 3, the contribution of brown adiposities in the post-surgical regulation of energy homeostasis will be determined. To do so, UCP1 knockout mice will be employed and RYGB-induced alterations in the in vivo metabolic rate, WAT and BAT phenotypes as well as WAT- and BAT-specific energy expenditures will be assessed and compared to those in their wild-type counterparts. With respect to expected outcomes, we anticipate that through induction and activation of brown adiposities, RYGB induces dramatic phenotypic and metabolic alterations in WAT and BAT. These alterations correlate with post-surgical augmentation of energy expenditure and hampering the brown adiposities induction blunts the therapeutic effects of the surgery significantly.
The future of the health of the population of the United States depends on identifying and providing effective treatment strategies for obesity. This proposal aims to shed light on the role of adipose tissue in regulating the metabolic rate and body weight after RYGB as well as the molecular pathways involved. The results will provide new target for the development of anti-obesity drugs.
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