Obesity continues to rise worldwide. Maternal obesity and consumption of high calorie diets continue to be public health concerns. The intrauterine and early postnatal environment provides support that is critical to the proper development and health of offspring. Maternal high fat (HF) diet consumption during pregnancy can have persistent detrimental effects on the fetus that predispose to obesity and its comorbidities. Our preliminary data in a rat model suggest that maternal HF diet has negative consequences on offspring controls of food intake via the gut- brain axis. Our overarching hypothesis is that gut dysbiosis resulting from perinatal exposure to maternal HF diet alters development of the gut-brain axis and vagally-mediated controls of feeding in offspring leading to increased susceptibility to obesity and other metabolic disorders. Aim 1 will determine how vagally-mediated controls of feeding are altered in rat offspring from dams consuming a HF during pregnancy and lactation. We hypothesize that HF offspring will be less sensitive to peripheral gut hormones, meal pre-loads, and/or nutrients that normally promote satiety. Aim 2 will determine how vagal communication between the gut and the brain is altered in HF offspring. We hypothesize that decreased satiation responses occur because (a) there is an alteration in the structure of VAN projections from the gut to the brain, (b) deficits in enteroendocrine cell number or function, and/or (c) the vagus nerve is less responsive to gut feedback signals. Aim 3 will define the role of gut microbiota composition in HF offspring propensity to obesity and other metabolic disorders. Our preliminary data indicate that HF offspring have gut dysbiosis and greater intestinal permeability by the time that they are weaned at postnatal day 21. Dysbiosis is sufficient to alter vagal structure and function, therefore we hypothesize that gut dysbiosis in HF offspring negatively affects gut-brain axis development and function. We will transfer dysbiotic HF microbiota to germ-free neonates to test sufficiency of dysbiosis in altered gut-brain axis function and determine whether use of prebiotics to normalize microbiota composition of HF fed dams, and consequently their offspring, will improve offspring gut-brain axis development and function. Together the proposed experiments will identify components of the gut-brain axis that are altered by early life exposure to maternal HF diet and could be targets for intervention to prevent adverse long-term metabolic consequences in HF offspring.
- Funder: NIH (via Johns Hopkins University)
- Amount: $902,749
- PI: Claire de La Serre