A Cohort Study of Weight Loss and Gliosis

April 7, 2023 updated by: Ellen Schur, MD, MS, University of Washington

A Twin Study of Obesity Pathogenesis Using fMRI

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

112

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Roz De Leon
  • Phone Number: 206-616-6360
  • Email: uwwebs@uw.edu

Study Locations

  • United States
    • Washington
      • Seattle, Washington, United States, 98109
        • University of Washington - South Lake Union

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

25 years to 64 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Aged 25-64 years
  • Behavioral Weight Loss (BWL) & Surgical Weight Loss (SWL) (Roux-en-Y Gastric Bypass (RYGB) or Sleeve Gastrectomy): BMI 30- <56 kg/m²
  • RYGB and Sleeve Gastrectomy: eligible for RYGB or Sleeve Gastrectomy and not undergoing revision or reoperation
  • Healthy Weight Controls (HWC): BMI 18.5-24.9 kg/m²

Exclusion Criteria:

  • Poorly controlled hypertension or coronary artery disease, or chronic disease (e.g. cancer, multiple sclerosis, autoimmune disease, rheumatic disease) Blood Pressure > 160/100 mmHG Heart Rate > 110 bpm
  • Chronic kidney disease (GFR <60 mL/min/1.73 m2),
  • Presence of cirrhosis (Nonalcoholic Fatty Liver Disease (NALFD)/Nonalcoholic Steatohepatitis (NASH) are acceptable),
  • Previous or planned (during the study period) obesity treatment with surgery (planned surgery ok for the SWL group) or a weight loss device. However, the following are allowed: (1) liposuction and/or abdominoplasty, if performed > 1 year before screening, (2) lap banding, if the band has been removed > 1 year before screening, (3) intragastric balloon, if the balloon has been removed > 1 year before screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year before screening,
  • A1c > 8.5% in Bariatric group; A1c ≥ 6.5% for BWL and HWC groups,
  • Current use of insulin (insulin ok for Surgical Weight Loss group, also called SWL), DPP-4 inhibitors, thiazolidinediones or medications known to alter metabolic function (e.g. atypical antipsychotics, corticosteroids),
  • Pregnancy or breastfeeding,
  • MRI contraindications (e.g. implanted metal, claustrophobia), or unable to have MRI or fit in MRI scanner
  • Current smoking/daily use of nicotine containing products (cigarettes, e-cigarettes, vaping or other nicotine containing products) or heavy alcohol use,
  • Weight >450 pounds (iDXA limit),
  • Weight-reduced from lifetime maximum weight by >16%,
  • Weight not stable over past 3 months (±10%),
  • T2D (for BWL or HWC),
  • Inability to participate in a weight loss program (BWL)
  • History of eating disorder or current eating disorder, currently enrolled in a weight loss program (ok for the SWL group provided weight stability and lifetime weight-reduced maximum conditions are met) or taking medications to lose weight
  • Severe food allergies
  • Any condition that the study physician determines to be unsafe for participation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Lifestyle Cohort
Participants Undergoing Behavioral Weight Loss Program
Behavioral: Behavioral Weight Loss Program
Behavioral Weight Loss Program is a modified version of the Diabetes Prevention Program (DPP).
Active Comparator: Surgical Cohort
Participants Scheduled for Roux-en-Y Gastric Bypass Surgery
Procedure: Roux-en-Y Gastric Bypass or Sleeve Gastrectomy
Subjects undergoing Roux-en-Y Gastric Bypass or Sleeve Gastrectomy with their own surgical team
No Intervention: Healthy Weight Control Cohort
Healthy Weight Controls With No Intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Weight Loss
Time Frame: During 6 Month Behavioral Weight Loss Program
During 6 Month Behavioral Weight Loss Program
Weight Regain
Time Frame: During 12-Month Follow-Up After Intervention
During 12-Month Follow-Up After Intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Washington

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Ellen Schur, MD, MS, University of Washington

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2019

Primary Completion (Anticipated)

June 30, 2024

Study Completion (Anticipated)

June 30, 2024

Study Registration Dates

First Submitted

June 25, 2018

First Submitted That Met QC Criteria

June 25, 2018

First Posted (Actual)

July 6, 2018

Study Record Updates

Last Update Posted (Actual)

April 11, 2023

Last Update Submitted That Met QC Criteria

April 7, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00002978
  • 2R01DK089036-06 (U.S. NIH Grant/Contract)
  • 1K24HL144917-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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