The long-term health benefits of obesity treatment are limited by the weight regain that almost universally follows a weight loss intervention, frustrating patients and clinicians alike. In lay terms, a new, higher ?set point? seems to occur after people gain weight, and research shows that processes of energy homeostasis, directed by neurons in the arcuate nucleus of the hypothalamus, vigorously defend the higher level of adiposity for years, promoting weight regain after behavioral weight loss. Bariatric surgery, however, results in weight loss that is more durable over time. These phenomena remain incompletely understood. The current proposal endeavors to address this crucial scientific gap by investigating the brain's role in the persistence of obesity and weight regain after weight loss. Specifically, studies in rodents show that diet-induced weight gain requires an inflammatory and cellular response, known as gliosis, within the arcuate nucleus of the hypothalamus and that this gliosis persists with continued dietary exposure. Importantly, gliosis is detectable in mice and humans by magnetic resonance imaging (MRI). Using MRI, the investigators discovered the first evidence of hypothalamic gliosis in obese humans. The investigators have also shown that hypothalamic gliosis is improved by Roux-en-Y gastric bypass (RYGB) surgery, suggesting that the efficacy and durability of weight loss via bariatric surgery could be partially explained by its ability to reverse gliosis. New findings show that hypothalamic gliosis negatively impacts brain regulation of appetite. Based on such findings, the proposed research investigates novel questions about the possible implications of hypothalamic gliosis for clinical weight management. First, it will determine whether the extent of hypothalamic gliosis present when people with obesity start a behavioral weight loss program is related to their success in treatment or weight regain after treatment. Second, the current proposal also addresses the question of whether gliosis is reduced to a greater extent when weight loss occurs by RYGB than by lifestyle change alone. Finally, this investigation uses a rodent study to test the role of 2 different hypothalamic glial cell types in weight regain after weight loss. In sum, basic science advances have identified hypothalamic cellular responses that facilitate weight gain during times of nutritional abundance, but this biological process is also capable of forming glial scars that are detrimental to neuronal functioning. The current research therefore investigates the implications of hypothalamic gliosis for humans undergoing obesity treatment. Achieving a better understanding of the role of the brain in successful obesity treatment could open new avenues for research, intervention, and prevention to alleviate the health risks of obesity.

Public Health Relevance

Obesity and the health complications of obesity are one of the most important public health concerns of our times. This research studies whether tissue damage within body-weight regulating areas of the brain makes obesity treatment less successful. It will advance the science of body weight regulation and may suggest avenues for developing novel strategies to prevent and/or treat obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089036-08
Application #
9972905
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Laughlin, Maren R
Project Start
2011-09-20
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Berkseth, Kathryn E; Rubinow, Katya B; Melhorn, Susan J et al. (2018) Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men. Obesity (Silver Spring) 26:1898-1904
Schur, Ellen; Carnell, Susan (2017) What Twin Studies Tell Us About Brain Responses to Food Cues. Curr Obes Rep 6:371-379
Melhorn, Susan J; Mehta, Sonya; Kratz, Mario et al. (2016) Brain regulation of appetite in twins. Am J Clin Nutr 103:314-22
Mestre, Zoe Lucille; Melhorn, Susan J; Askren, Mary K et al. (2016) Effects of Anxiety on Caloric Intake and Satiety-Related Brain Activation in Women and Men. Psychosom Med 78:454-64
Bosch, Tyler A; Chow, Lisa; Dengel, Donald R et al. (2015) In adult twins, visceral fat accumulation depends more on exceeding sex-specific adiposity thresholds than on genetics. Metabolism 64:991-8
Schur, Ellen A; Melhorn, Susan J; Oh, Seok-Kyun et al. (2015) Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans. Obesity (Silver Spring) 23:2142-8
Berkseth, Kathryn E; Guyenet, Stephan J; Melhorn, Susan J et al. (2014) Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinology 155:2858-67
Melhorn, Susan J; Tyagi, Vidhi; Smeraglio, Anne et al. (2014) Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans. Appetite 82:85-90
Springer, Alyse M; Foster-Schubert, Karen; Morton, Gregory J et al. (2014) Is there evidence that estrogen therapy promotes weight maintenance via effects on leptin? Menopause 21:424-32
Myhre, Rachel; Kratz, Mario; Goldberg, Jack et al. (2014) A twin study of differences in the response of plasma ghrelin to a milkshake preload in restrained eaters. Physiol Behav 129:50-6

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