Bariatric surgery is increasingly used for the treatment of obesity and associated type-2 diabetes, but the mechanisms for the beneficial effects are not well understood. Recent clinical studies show that the large early suppression of food intake may be more important for remission of the diabetic state than previously assumed, as pair-feeding non-surgical control subjects to the low level of food intake of gastric bypass patients improved glycemic control just as much. However, dieting typically fails because of increased hunger and reduced metabolism - counter-regulatory responses that are suspiciously absent after bypass surgery. Here, in a new mouse model for Roux-en-Y gastric bypass surgery (RYGB), we focus on the potential mechanisms responsible for keeping the strong hunger drive in check. Preliminary observations in RYGB mice and rats show that: (a) eating a meal excessively activates calcitonin-gene- related peptide-expressing neurons in the external lateral parabrachial nucleus, (b) reduced food intake is the result of smaller meal size and early satiety, and (c) food choice gradually shifts from high-fat to low-fat foods. We hypothesize that the brainstem "anorexia pathway" centered around the lateral parabrachial nucleus is critically involved in the reduced food intake after RYGB and that the anorexic power of this neural pathway can be leveraged to prevent and reverse obesity without surgery. To this end, we will identify the critical components of the anorexia pathway in Aim 1. We will test the hypothesis that inhibition of the anorexia pathway moderates the reduction in food intake and weight loss after RYGB in Aim 2. Finally, we will test the ability of chronically stimulating the anorexia pathway to prevent or reverse high-fat diet- induced obesity and to prevent weight regain after calorie restriction-induced weight loss in non- surgical animals in Aim 3. Neuron- and site-specific inhibition and stimulation of the anorexia pathway will be achieved by novel pharmacogenetic manipulations. The results of these studies have the potential to identify some critical neural and behavioral mechanisms that make bariatric surgeries so efficient and to translate these mechanistic insights into new pharmacological and behavioral anti-obesity therapies.

Public Health Relevance

Bariatric surgery is currently the most effective treatment of obesity and its associated health problems such as diabetes, cardiovascular disease, and sleep disturbances. This proposal investigates neural mechanisms responsible for the surgery-induced reduction in appetite and body weight, so that new pharmacological and behavioral treatments can be developed without the need for surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK047348-19
Application #
8709187
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Serrano, Jose
Project Start
1994-08-20
Project End
2019-03-31
Budget Start
2014-05-01
Budget End
2015-03-31
Support Year
19
Fiscal Year
2014
Total Cost
$321,900
Indirect Cost
$104,400
Name
Lsu Pennington Biomedical Research Center
Department
None
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Yu, Sangho; Qualls-Creekmore, Emily; Rezai-Zadeh, Kavon et al. (2016) Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis. J Neurosci 36:5034-46
Münzberg, Heike; Qualls-Creekmore, Emily; Berthoud, Hans-Rudolf et al. (2016) Neural Control of Energy Expenditure. Handb Exp Pharmacol 233:173-94
Morrison, Christopher D; Hao, Zheng; Mumphrey, Michael B et al. (2016) Roux-en-Y gastric bypass surgery is effective in fibroblast growth factor-21 deficient mice. Mol Metab 5:1006-14
Hao, Zheng; Mumphrey, Michael B; Townsend, R Leigh et al. (2016) Reprogramming of defended body weight after Roux-En-Y gastric bypass surgery in diet-induced obese mice. Obesity (Silver Spring) 24:654-60
Hao, Zheng; Mumphrey, Michael B; Townsend, R Leigh et al. (2016) Body Composition, Food Intake, and Energy Expenditure in a Murine Model of Roux-en-Y Gastric Bypass Surgery. Obes Surg 26:2173-82
Mumphrey, M B; Hao, Z; Townsend, R L et al. (2016) Eating in mice with gastric bypass surgery causes exaggerated activation of brainstem anorexia circuit. Int J Obes (Lond) 40:921-8
Laeger, Thomas; Albarado, Diana C; Burke, Susan J et al. (2016) Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2. Cell Rep 16:707-16
Hao, Z; Münzberg, H; Rezai-Zadeh, K et al. (2015) Leptin deficient ob/ob mice and diet-induced obese mice responded differently to Roux-en-Y bypass surgery. Int J Obes (Lond) 39:798-805
Münzberg, H; Laque, A; Yu, S et al. (2015) Appetite and body weight regulation after bariatric surgery. Obes Rev 16 Suppl 1:77-90
Mumphrey, Michael B; Hao, Zheng; Townsend, R Leigh et al. (2015) Sleeve Gastrectomy Does Not Cause Hypertrophy and Reprogramming of Intestinal Glucose Metabolism in Rats. Obes Surg 25:1468-73

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