Thermogenic Silencer Regulatory Factors in Humans

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Age between 18 years old and 35
2. Lean group: BMI is between 18.5 and 24.9. HgA1c \<5.7%
3. Obese group: BMI is \>30, HgA1c \<5.7%
4. Obese group with Type II diabetes: BMI is \>30, HgA1c is \>6.5% If on oral medication for diabetes management, HgA1c may be \< 6.5% The following medications are also acceptable: statins, aspirin, angiotensin-converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARB).

Exclusion Criteria:

1. Diabetes type I (self-report)
2. Diagnosis of thyroid disease (including goiter, hyperthyroidism, hypothyroidism, thyroiditis)(self-report)
3. Diagnosis with cancer including skin cancer (self-report)
4. Diagnosis or evidence of Raynaud's Syndrome or systemic sclerosis (self-report)
5. A recent diagnosis of Coronavirus Disease 2019 (COVID-19) (last 2 weeks) or hospitalized at the time of diagnosis with COVID-19
6. Any vaccine administration within two weeks preceding the study procedure
7. Currently pregnant
8. Currently taking any prescribed medication other than oral contraceptives. Treatments for weight loss or any other supplements that may alter weight or metabolism are not acceptable. Vitamins are acceptable.
9. Has consumed nicotine (smoking, inhaling, ingesting) within the last 6 months
10. Has used illicit drugs within the last 6 months (marijuana users are eligible unless consumed in the last 30 days).
11. Any medical, psychological, or social condition that, in opinion of principle investigators, would jeopardize the health or well-being of the participant during the study procedure or the integrity of the data
12. Diabetes Type II that is managed by insulin.
13. Steroid use in the last 30 days to the exclusions