NCT06424132

Thermogenic Silencer Regulatory Factors in Humans

Identification of Thermogenic Silencing Regulatory Factors as Biomarkers of Metabolic Health in Humans

• Status: Active Not Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 8 (actual)
• Sponsor: Rockefeller University · Academic / Other
• Sex: All
• Age: 18 Years – 35 Years
• Healthy volunteers: Accepted

Summary

A promising approach to correct the metabolic dysfunction associated with obesity is to activate brown fat non-shivering thermogenesis (NST). A critical limitation with NST as a therapeutic option, however, is that this beneficial process is silenced under human physiological temperature conditions and the mechanisms of how this occurs is unknown. This study will be the first to identify human NST silencing factors that may be targeted for the treatment of obesity and metabolic disorders.

Detailed description

Obesity and associated metabolic diseases such as type 2 diabetes continue to be one of the leading causes of death worldwide, demanding additional research into novel treatments beyond our current options. One promising experimental approach to overcome the metabolic dysfunctions associated with obesity, such as insulin resistance and glucose imbalance, is to activate brown fat non-shivering thermogenesis (NST). Activated human brown adipose tissue (BAT) increases energy expenditure at a molecular level and is associated with both improved insulin tolerance and glucose homeostasis. A critical limitation with human brown fat as a therapeutic option, however, is that its beneficial metabolic potential is restricted in a silenced state under physiological temperature conditions for most of human life. The regulatory factors that govern this silencing process are completely unknown. While many groups continue to seek novel mechanisms to activate brown fat, this study presents a unique approach, aiming to decipher the mechanisms that govern human brown fat silencing. The study hypothesizes that if the regulatory factors that silence brown fat NST can be defined, then these factors can be targeted for ablation to eliminate the "off switch", thereby keeping brown fat in a constitutively active state. Identification of human NST silencing factors will be critical to unlocking the metabolic benefits of human brown fat and would represent promising treatment opportunities for type 2 diabetes and other obesity-related disorders. Understanding these relationships will allow for precision treatment opportunities for type 2 diabetes in the future. The overall goal of this study is to unlock the metabolic benefits of human brown fat by defining the regulatory mechanisms that keep BAT in a silenced state. The study will generate the first human secretome (list of secreted proteins in blood) and transcriptome (list of gene transcripts in adipose tissue) compendium from human plasma and subcutaneous adipose tissue respectively which will be composed of target proteins, metabolites, and genes that are differentially expressed in response to NST silencing conditions. Top candidates from the profiling will then be functionally validated in human adipocytes for their role in NST silencing. The study will be an important resource for the field and will identify novel candidates that may harbor regulatory potential to govern the NST silencing process in humans. These factors can then be targeted to promote the constitutive activation of NST in order to overcome the metabolic dysfunction associated with obesity and metabolic disease. Given the invasive nature of direct human brown fat sampling, the study will instead interrogate circulating factors in human plasma as a proxy for metabolic health. In addition, the study will also obtain subcutaneous adipose tissue for RNA profiling to identify genes that are upregulated under NST-silenced conditions compared to cold exposure.

Conditions

• Obesity
• Metabolic Disease
• Cold Exposure

Interventions

Type	Name	Description
OTHER	Cold Vest Exposure Period	A cold vest will be placed on the participant which consists of a water-perfused wearable vest, size S-M or M-L with adjustable straps attached to a small 'cooler' reservoir to circulate cold water between the vest and the cooler (Polar Products, Stow, OH- Product link: www.polarproducts.com/polarshop/pc/CoolOR-13-Quart-System-with-Arctic-Chiller-p24757.htm) This product is safe and recommended by experimental guidelines for human BAT studies. Participants will be cold exposed for a period of 3 hours resting in a reclined position engaged in reading and/or digital entertainment of their choice.
OTHER	Rewarming Exposure Period	Following cold exposure, the cold vests will be removed, and participants will be offered a warm blanket to ease the transition from cold back to warm temperatures. Participants will then be moved to an adjacent warm room maintained at 30 degrees celsius and asked to return to the resting position of their choice. Participants will then engage in reading and/or digital entertainment for a 3-hour warm exposure period.
OTHER	Fasting	Participants will be requested to refrain from food and caloric drinks for 12 hours (starting at 8pm) prior to the study visit. Blood will then be drawn the following morning (between 8 and 9am) 30mins later following a breakfast meal (9:30am- 10am). Participants will be housed in a room with ambient temperature at 25 degrees celsius between the two blood draws.

Timeline

• Start date: 2024-08-16
• Primary completion: 2026-12-04
• Completion: 2026-12-04
• First posted: 2024-05-21
• Last updated: 2026-04-14

Locations

1 site across 1 country: United States