Understanding the Initiation and Progression of Diet-Induced Obesity and Associated Pathophysiology: Lessons Learned from a Rat Model

In human populations, the development and progression of obesityObesity and its consequences on host systems is complex. Risk for obesityObesity can reside in an individual’s genome, in epigeneticEpigenetic modifications, and in dietary and activity level variables. In addition to host system factors, the dietDiet can also influence the gut microbiota leading to alterations to the host and such alterations can contribute to pathophysiological sequelae in the host. In order to better understand the impact of dietDiet on obesityObesity development, our group has studied the consequences of a high-fat/high-sucrose (HFS) dietDiet on physiological systems of Sprague-Dawley male rats over short term and long term exposure to the dietDiet. Medium (12 weeks) to long term (28 weeks) exposure to the dietDiet leads to development of knee, shoulder, and to a lesser degree, hip damage, alterations to some skeletal musclesSkeletal muscle, development of insulin resistanceInsulin resistance and type 2 diabetesDiabetes, development of features of systemic metabolic syndromeMetabolic syndrome, fatty liver disease, and alterations to the vitreous humor of the eye. Very short time exposure (days to 4 weeks) leads to early, but fluctuating changes to serum cytokineCytokines profiles, changes to some skeletal musclesSkeletal muscle, and the onset of knee joint damage. Alterations to the gut microbiota are evident following medium to longer term exposure to the dietDiet, but not during the shorter time frame. Exposure of rats on the HFS dietDiet to either a modest exerciseExercise protocol or an oligofructose prebioticPrebiotics initiated at the same time as the HFS dietDiet is initiated, completely prevented development of joint damage at 12 weeks. Thus, the development of obesityDevelopment of overweight or obesity, and at least some of its pathophysiological sequelae in this model, are modifiable by low cost, minimally invasive interventions. Such findings provide an opportunity to determine whether some of the consequences of exposure to the HFS dietDiet develop in parallel or serially, and to identify potential points in the process that are reversible. Current studies are focused on addressing such questions.