Efficacy of Pharmacological Stimulation of BAT and WAT in Lean and Obese Young Adults (MiraBAT)

Efficacy of Pharmacological Stimulation of Brown and White Fat in Lean and Obese Young Adults

To determine whether pharmacological stimulation of supraclavicular Brown Adipose Tissue (BAT or "Brown Fat") and subcutaneous White Adipose Tissue (WAT) using an FDA-approved beta3 agonist is as effective in increasing oxidative metabolism in BAT and WAT as is the exposure to cold, the investigators will assess the efficacy of an FDA approved beta3 agonist Mirabegron (trade name Myrbetriq, Astellas Pharma, Inc.) for increasing oxidative metabolism in supraclavicular BAT and subcutaneous WAT in lean and obese young adults.

The investigators anticipate that both methods to stimulate supraclavicular BAT and subcutaneous WAT will result in similar 18F-labeled fluoro-deoxyglucose (FDG) tracer uptake on positron emission tomography (PET) images as well as oxidative metabolism. This would demonstrate that pharmacological stimulation of BAT is effective and could lead to further, more detailed clinical trials in obese subjects.

Study Overview

• Status: Unknown
• Conditions: Brown Fat
• Intervention / Treatment: Drug: Mirabegron; Other: Cold exposure

Detailed Description

Obesity and diabetes have increased to epidemic proportions in the US and in many other countries. In addition, the comorbidities of these metabolic diseases, such as cardiovascular disease, cancer, osteoarthritis are placing a huge burden on the health and health care system of the United States. Finding new avenues for human therapeutics is thus a critical challenge. Brown adipose tissue (BAT or "Brown Fat") functions to dissipate stored chemical energy in the form of heat and serves to defend mammals from hypothermia and obesity.

It is now firmly established that humans have functional BAT that can be activated by mild cold stress and imaged by 18F-labeled fluoro-deoxyglucose (FDG) PET imaging. Moreover, it is now understood that there are two distinct types of brown fat cells: the "classical" brown fat (most common in supraclavicular fat depots) that form developmentally from a muscle-like myf5-positive lineage and brown fat cells that can appear in white adipose tissue (WAT) depots upon prolonged exposure to cold or beta-adrenergic signaling. These latter cells originate from a myf5-negative lineage and are referred to as beige cells. Recent data suggests that most adult humans might have both brown and beige fat cells that are inactive but could be activated via the adrenergic system. Once activated, thermogenesis in these cells could affect the body's energy balance and might be instrumental in weight management.

Although adrenergic activation using cold exposure has been shown to be highly effective in activating both brown and beige fat cells, it is difficult to implement in daily routine and there is a need for other, more practical, interventions. Mirabegron (trade name Myrbetriq, Astellas Pharma, Inc.) is a drug for the treatment of overactive bladder which was FDA approved in July of 2012. Mirabegron activates the beta3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. There are reports of increased BAT FDG uptake following MIrabegron administration in both rodents and recently in humans. Because pharmacological stimulation of brown/beige fat cells might increase daily energy expenditure, this might represent a novel mechanism for weight management and eventually a new avenue for the treatment for obesity.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Children's Hospital of Michigan
      • Contact: Otto Muzik, PhD; Phone Number: 313-993-2616; Email: otto@pet.wayne.edu
      • Contact: Cynthia Burnett, MS,CJ; Phone Number: 313-993-3848; Email: cgburnet@med.wayne.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• BMI < 25 kg/m2 or BMI > 30 kg/m2
• Able to give study-specific informed consent
• Able to tolerate PET/CT imaging required by protocol, to be performed without sedation and
• Patients who are not on sedative, antidepressant, sedative antihistaminic or narcotic medications.

Exclusion Criteria:

• Subjects of reproductive potential, who are sexually active but unwilling and/or unable to use medically appropriate contraception, or women who are pregnant or breastfeeding
• Subjects with cardiac disease or hypertension
• Subjects with history of diabetes
• Subjects with severe renal impairment or subjects with moderate hepatic impairment
• Subjects with severe uncontrolled hypertension.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Subjects that undergo both cold exposure and one-time dose of 100mg of Mirabegron drug	Drug: Mirabegron; One-time dose of 100mg of Mirabegron; Other Names: Myrbetriq; Other: Cold exposure; Exposure of subjects to cold temperature to induce non-shivering thermogenesis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SUV as a measure of glucose metabolism	SUV value in supraclavicular BAT and subcutaneous WAT	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Flow	Blood Flow in supraclavicular BAT and subcutaneous WAT	4 hours

Collaborators and Investigators

• Sponsor: Otto Muzik
• Investigators: Principal Investigator: Otto Muzik, Wayne State University

Publications and helpful links

General Publications

• Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab. 2015 Jan 6;21(1):33-8. doi: 10.1016/j.cmet.2014.12.009.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Anticipated): October 1, 2017
• Study Completion (Anticipated): March 1, 2018

Study Registration Dates

• First Submitted: January 22, 2015
• First Submitted That Met QC Criteria: January 29, 2015
• First Posted (Estimate): February 3, 2015

Study Record Updates

• Last Update Posted (Actual): May 10, 2017
• Last Update Submitted That Met QC Criteria: May 8, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: BAT activation; quantitative PET imaging; Mirabegron effect on BAT
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Adrenergic beta-3 Receptor Agonists; Mirabegron
• Other Study ID Numbers: WSU_OVPR1