Incretins, the analogs of glucagon-like peptide-1 (GLP-1), improve glucose control in type 2 diabetes mellitus and counteract obesity through mechanisms that are not completely understood. Our preliminary data show that, in prediabetic patients and mice, GLP-1 analog therapy induces an increase in plasma IL-6, a cytokine activating STAT3 signaling, which induces brown (beige) adipocyte differentiation in adipose tissue (AT). We discovered that plasma IL-6 induction occurs through GLP-1 receptor (GLP-1R) stimulation in leukocytes. Interestingly, studies in rodents indicate that GLP-1 / GLP-1R signaling also induces AT beiging. Based on these observations, we hypothesize that incretins induce AT browning in part via transient IL-6 / IL-6R / STAT3 signaling. Our primary objective is to further elucidate the role of IL-6 and GLP-1 signaling in mediating beneficial metabolic effects of incretin therapy. Our studies will be paralleled in a human clinical trial, a human cell culture model, and a mouse diet-induced obesity model. GLP-1 analog therapy combined with an IL-6 blocking antibody will be used.
Specific Aim 1 is to (A) investigate IL-6 induction / downstream STAT3 signaling and AT browning upon incretin therapy in prediabetic human patients; and (B) validate mice as a model to study incretin-induced IL-6 signaling as a mediator of AT browning.
Specific Aim 2 is to (A) investigate if GLP-1 analog effects on beige adipogenesis depend on IL-6 signaling in human adipocyte progenitors; and (B) investigate if GLP-1 analog effects on beige adipogenesis depend on IL-6 signaling in mice. We expect to discover that 1) GLP-1 analog signaling via GLP- 1R induces IL-6 secretion by leukocytes, and 2) GLP-1 analog therapy induces adipose tissue browning via both direct GLP-1 / GLP-1R signaling and indirect incretin-induced IL-6 / IL-6R / STAT3 signaling. The results of this novel study will give critical insights on the anti-obesity mechanisms of GLP-1 analogs and serve as the basis for developing more targeted therapies for diabetes and obesity. Understanding the anti-diabetic IL-6 effects will also be important for interpreting the results of IL-6 blockade, a therapeutic approach for patients with diabetes and other inflammatory conditions, which may need to be re-considered.

Public Health Relevance

This project investigates the anti-obesity mechanisms of glucagon-like peptide-1 (GLP-1) analogs, which are used in the treatment of human obesity and diabetes mellitus. We will test if GLP-1 induces secretion of interleukin-6 (IL-6), a cytokine that may collaborate with GLP-1 analogs to induce the formation of brown fat, which has anti-diabetic properties. Our results will guide future obesity and diabetes mellitus therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK122234-02
Application #
10015259
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Serrano, Katrina Jane
Project Start
2019-09-10
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030