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mTORC1 and Autophagy in Human Brown Adipocytes (mTORHBFC)

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ClinicalTrials.gov Identifier: NCT04206124
Recruitment Status : Recruiting
First Posted : December 20, 2019
Last Update Posted : December 20, 2019
Sponsor:
Information provided by (Responsible Party):
Meilian Liu, University of New Mexico

Brief 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.

Condition or disease Intervention/treatment Phase
Obesity Metabolic Disease Procedure: Brown Fat Harvest During Anterior Neck Surgery Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: N/A
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
Official Title: Regulation of Beige Fat Development by mTORC1 and Autophagy
Actual Study Start Date : November 1, 2016
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2023

Arm Intervention/treatment
Experimental: Single Arm Study Group
Includes all consented patients, male and female, undergoing anterior cervical spine surgery, parathyroidectomy or thyroidectomy (18-60 years old), without history of diabetes mellitus and not pregnant or incarcerated.
Procedure: Brown Fat Harvest During Anterior Neck Surgery
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.




Primary Outcome Measures :
  1. Protein expression levels in lean and obese human brown adipose tissue samples will be quantified via Western Blot and comparatively analyzed using a student T-test. [ Time Frame: Up to six years after date of sample collection. ]

    Human brown adipose tissue (BAT) samples will be collected during previously scheduled anterior neck surgery and then cultured and amplified for experiments including Western Blot (WB), an assay to quantify the relative amounts of protein present in a sample.

    WB will be used to determine how protein expression levels differ between lean and obese BAT samples. Specifically, the translational levels of key markers of mTOR signaling including UCP1, C/EBPβ, HSL, S6K, ADPN, PKA, AMPK and ATGL will be quantified by WB and analyzed statistically using student T-test, and protein activation levels will be quantified by dividing phosphorylated protein content by total protein content.


  2. Gene transcript expression levels in lean and obese human brown adipose tissue samples will be quantified via quantitative Polymerase Chain Reaction and comparatively analyzed using a student T-test. [ Time Frame: Up to six years after date of sample collection. ]

    Human brown adipose tissue (BAT) samples will be collected during previously scheduled anterior neck surgery and then cultured and amplified for experiments including quantitative-Polymerase Chain Reaction (q-PCR), an assay to quantify the relative amounts of mRNA (transcribed genes) present in a sample.

    q-PCR will be used to determine how gene expression levels differ between lean and obese BAT samples. Specifically, the transcriptional levels of key markers of mTOR signaling including UCP1, C/EBPβ, HSL, S6K, ADPN, PKA, AMPK and ATGL will be quantified by q-PCR and analyzed using student T-test.




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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male or Female
  • age 18-60
  • able to give informed consent
  • non-diabetic
  • scheduled for anterior cervical spine, thyroidectomy, or parathyroidectomy surgery at UNMHSC
  • BMI <25 (lean) or >30 (obese)
  • English or Spanish speaking

Exclusion Criteria:

  • has diabetes mellitus (type I or II)
  • currently on any study medication (including sedatives or analgesics, coagulopathy (INR of 1.5 or greater, platelet count of <50,000/microliter), or anticoagulant)
  • pregnant
  • incarcerated

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04206124


Contacts
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Contact: Meilian Liu, PhD 5052724036 meilianliu@salud.unm.edu
Contact: Lily Elizabeth Feldman 8025223687 feldman.lily@gmail.com

Locations
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United States, New Mexico
University of New Mexico Health Sciences Center Recruiting
Albuquerque, New Mexico, United States, 87131
Contact: Meilian Liu, PhD    505-272-4036    meilianliu@salud.unm.edu   
Contact: Lily Elizabeth Feldman    8025223687    feldman.lily@gmail.com   
Sponsors and Collaborators
University of New Mexico
Investigators
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Principal Investigator: Meilian Liu, PhD University of New Mexico Biochemistry & Molecular Biology
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Responsible Party: Meilian Liu, Associate Professor, University of New Mexico
ClinicalTrials.gov Identifier: NCT04206124    
Other Study ID Numbers: 14-272
First Posted: December 20, 2019    Key Record Dates
Last Update Posted: December 20, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Participant data will be de-identified after specimen collection. De-identified data will be stored securely and not shared with other researchers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Meilian Liu, University of New Mexico:
Autophagy
Inflammation
Metabolism
Adipocyte
mTORC1
Obesity
Thermogenesis
Additional relevant MeSH terms:
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Metabolic Diseases