mTORC1 and Autophagy in Human Brown Adipocytes
Condition: Obesity; Metabolic Disease
MeSH terms: Metabolic Diseases
Study type: Interventional

Summary: 
      The long term goal is to identify the potential therapeutic targets for the treatment of
      obesity and its associated disorders by studying the driving factors of activation of brown
      adipose tissue (BAT) in human adults. Whereas activation of brown adipose tissue (BAT) in
      human adults has been considered as a potential therapeutic target to battle obesity since it
      was identified in 2009, the underlying mechanisms of beige adipocytes appearance in human
      adults is unclear. The objective of this proposal is to investigate the role of autophagy in
      mediating the inhibitory effect of mammalian target of rapamycin complex 1 (mTORC1) in
      regulating human brown adipocytes. The central hypothesis is that autophagy plays a critical
      role in regulating browning of white adipose tissue and mediates the beneficial effect of
      mTORC1 inhibition on thermogenesis in human brown adipocytes.
    

Detailed description: 
      Specific Aim 1: To investigate the role of mTORC1 and autophagy in regulating thermogenesis
      in human brown adipocytes. The working hypothesis is that inhibition of mTORC1 or activation
      of autophagy improves thermogenesis in human brown adipocytes. It will be first determined if
      the mTORC1/autophagy signaling modulates thermogenic gene expression and beige markers by
      collecting human brown fat from lean non-diabetic subjects. The brown fat during the anterior
      cervical spine surgery or thyroidectomy from lean subjects with a BMI <25, or obese
      participants who have a BMI >30, will be harvested and then be used to determine: 1) whether
      mTORC1 signaling, autophagy and thermogenic gene expression, and the fraction of various
      types of immune cells in human brown fat are different from those in rodents;2) whether
      rapamycin treatment enhances basal or CL-induced thermogenic gene expression and O2
      consumption in primary human brown adipocytes; and 3) whether inhibition of autophagy by
      3-methyladenine (3-MA) suppresses thermogenic gene expression induced by CL316,243, a
      β3-adrenoceptor agonist that mimics cold stress in vivo in human brown adipocytes.

      Overall, this study will lead to the identification of mTORC1 as a key regulator of
      thermogenesis in human adipose tissue and reveal promising new anti-obesity drug targets. In
      addition, this study will further investigate the role of rapamycin administration in obesity
      in human adults near the future. These studies are designed to be a proof-of-principle. If
      the results are promising, then future drug development could focus on designing new
      inhibitors of mTORC1.
    

Intervention name(s): Brown Fat Harvest During Anterior Neck Surgery
Intervention type(s): Procedure
Intervention description(s): During previously indicated thyroid gland removal or anterior cervical spine surgery, as scheduled at UNMHSC, the surgeon will identify the large muscle on the side of the neck in the surgical field. Using minimal dissection adjacent to the muscle, they will then remove 5-10mg of brown fat from this region. These samples will be further analyzed using various biochemical tools.
Intervention model: Single Group Assignment
Intervention model description: Patients will be recruited based on sex, age, and medical history including BMI (lean, <25, or obese, >30), medication list, and health status. Included patients indicated for thyroidectomy, parathyroidectomy, or cervical spine injury surgery, who are able to consent, will have a soybean-sized amount of brown fat removed from the neck during surgery. These tissue samples will be further analyzed using biochemical tools after being de-identified from patient records.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Autophagy; Inflammation; Metabolism; Adipocyte; mTORC1; Obesity; Thermogenesis