A Cohort Study of Weight Loss and Gliosis

Summary

Patients and clinicians need better options to prevent the weight regain that almost universally follows a weight loss intervention. In lay terms, a new, higher "set point" seems to occur after people gain weight. Evidence from some research studies reinforces these observations, showing that processes of energy homeostasis vigorously defend the higher level of adiposity for years, if not permanently. Only bariatric surgery appears to "re-set" to a lower level of adiposity. No clear mechanism has been elucidated to date that explains these phenomena. The current proposal endeavors to address this crucial scientific gap by translating preclinical data into human studies testing novel mechanistic hypotheses. Prior studies in rodents show that a high-fat diet causes inflammation and a cellular response, known as gliosis, within hypothalamic regions regulating energy balance and glucose homeostasis. Evidence further suggests that gliosis might play a pathogenic role in obesity and type 2 diabetes mellitus (T2D) because its development precedes weight gain and impaired glucose homeostasis and its inhibition improves metabolic health. Importantly, gliosis is detectable in mice and humans by magnetic resonance imaging (MRI). Using MRI, the investigators discovered the first evidence of gliosis in obese humans and went on to show associations of gliosis with insulin resistance in humans, independent of the level of adiposity. New findings suggest that people with T2D have more extensive gliosis than is seen in nondiabetic obese subjects. Further findings reveal that gliosis improves, but is not completely reversed, 8 mo. after Roux-en-Y gastric bypass (RYGB) surgery in T2D patients. It remains unknown whether gliosis improves similarly when weight loss occurs by lifestyle change or if the efficacy and durability of weight loss via bariatric surgery is partially explained by its ability to reverse gliosis via an as yet unknown mechanism of action. We therefore propose three studies in humans to discover 1) if hypothalamic gliosis is reversed by a standard behavioral weight loss intervention, 2) if the extent of gliosis predicts successful weight loss during, or weight regain after, behavioral weight loss, and 3) the time course of improvement in gliosis after RYGB and the relation of its improvement to the short- and long-term efficacy of RYGB. Future research would define dietary, environmental, or other risk factors for the development of hypothalamic gliosis in humans. Achieving a better understanding of the role of the brain in obesity and its treatment could open new avenues for research, intervention, and prevention.

Conditions

• Obesity, Gliosis, Weight-Loss

Interventions

BEHAVIORAL

Behavioral Weight Loss Program

Behavioral Weight Loss Program is a modified version of the Diabetes Prevention Program (DPP).

PROCEDURE

Roux-en-Y Gastric Bypass or Sleeve Gastrectomy

Subjects undergoing Roux-en-Y Gastric Bypass or Sleeve Gastrectomy with their own surgical team

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  collaborator NIH

• National Heart, Lung, and Blood Institute (NHLBI)

  collaborator NIH

• University of Washington

  lead OTHER

Principal Investigators

• Ellen Schur, MD, MS · University of Washington

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

25 Years

Max Age

64 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2019-06-01

Primary Completion

2024-06-30

Completion

2025-06-30

Countries

• United States

Study Locations