A8 - Reversal of Hypothalamic/Midbrain Inflammation and Restoration of Central Leptin Sensitivity as a Driver of Sustained Weight Loss
The increased accessibility of palatable, calorie-dense foods represents a major predisposing environmental factor for the development of obesity. Chronic over-nutrition leads to a state of hypothalamic inflammation, central leptin and insulin resistance, subsequent hyperphagia and weight gain. Similar pathological sequelae may also take place in dopaminergic neurons in the midbrain, thereby impacting on the hedonic aspects of feeding. We have previously shown, using a rodent bariatric surgical model, that striatal dopamine signaling is modified postoperatively due to changes in intestinal nutrient sensing, and that this underlies healthier fat appetite. We will continue working with this rodent bariatric surgical model to study the possible differential influences of weight loss following surgery vs. chronic food restriction on high fat diet-induced inflammatory processes in homeostatic and hedonic feeding circuits and focus on the underlying mechanisms. We will then translate these findings by performing human studies.
Weight regain following dieting has been attributed to altered gut microbiota and adipocyte signaling. Relatively few studies have evaluated the impact of bariatric surgery on gut microbiota and adipocytes and how this may influence adipose tissue communication to the brain. We have previously shown using our rodent bariatric surgical model that thermogenic gene expression in brown adipocytes is affected, possibly underlying increased energy expenditure postoperatively. We will also take advantage of our rodent bariatric surgical model to study the possible differential influences of weight loss following surgery vs. chronic food restriction on adipocyte morphology and gene expression. Special emphasis will be placed on alterations in gut-adipose tissue signaling after bariatric surgery in order to gain mechanistic insights into how a new adiposity set-point develops. We will then translate these findings using human adipose tissue samples.
Figure 1: Gastric bypass surgery and chronic food restriction may impact differentially on gut-brain and gut-adipose tissue-brain communication through parallel and redundant pathways to exert distinct long-term influences on feeding behavior and body weight.
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