Thesis
The effects of ceramide regulated bone morphogenetic protein 3 on adipocyte metabolism
University of Iowa
Master of Science (MS), University of Iowa
Spring 2024
DOI: 10.25820/etd.007341
Abstract
Obesity is responsible for the development of various metabolic diseases like type 2 diabetes and cardiovascular disease costing the US healthcare system $147 billion a year. Overnutrition in obesity leads to the excess accumulation of fats in tissues not suited for lipid storage. This spillover of fats into non-adipose tissues causes harmful effects in those tissues, a condition known as lipotoxicity. Ceramides are a class of sphingolipids that is synthesized under these obesogenic conditions and impairs insulin signaling and mitochondrial function. To better understand the downstream mechanisms of ceramides in adipose tissue, we used transcriptomic screens and identified a ceramide-regulated protein called Bone Morphogenetic Protein 3 (Bmp3). Bmp3 is known for its role in bone formation and embryonic development, but recently it has been found to be elevated in adipose tissue. PURPOSE: The purpose of this study is to determine the effects of ceramide-regulated Bone Morphogenetic Protein 3 in adipocyte metabolism as well as in energy and glucose homeostasis. METHODS: We generated a new mouse model to overexpress Bmp3. We generated an adeno-associated virus (AAV) that encodes the full length of mouse Bmp3 or enhanced green fluorescent protein (eGFP) under a human thyroxine-binding globulin (TBG) promoter. Six-week-old C57BL/6J male mice were injected with 1x1011 particles through retro-orbital injection to help induce force production of Bmp3. These overexpression mice were subjected to experiments under sub-chronic and chronic conditions to observe the effects of Bmp3 on adipose tissue homeostasis as well as energy and glucose metabolism. We also generated an inducible UCP1+ thermogenic adipocyte-specific loss-of-function mice for Bmp3 to observe the effects of Bmp3 on thermogenic genes. RESULTS: Our findings show that Bmp3 is sufficient to impair thermogenesis and glucose and energy homeostasis in obese mice. Moreover, we find that ablation of Bmp3 in Ucp1+ thermogenic adipocytes improves energy and glucose homeostasis. DISCUSSION: Currently, ceramide regulation of Bmp3 is poorly understood with no known studies on Bmp3 in adipose tissue. Our findings indicate that Bmp3 regulates adipose homeostasis and obesity by negatively regulating adaptive thermogenesis.
Details
- Title: Subtitle
- The effects of ceramide regulated bone morphogenetic protein 3 on adipocyte metabolism
- Creators
- Aaron Tran
- Contributors
- Bhagirath Chaurasia (Advisor)Vitor Lira (Committee Member)Gary Pierce (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Health and Human Physiology
- Date degree season
- Spring 2024
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007341
- Number of pages
- viii, 25 pages
- Copyright
- Copyright 2024 Aaron Tran
- Language
- English
- Date submitted
- 04/17/2024
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (page 24-25).
- Public Abstract (ETD)
Obesity is responsible for the development of various metabolic diseases like type 2 diabetes and heart disease, costing the US healthcare system $147 billion a year. The consumption of more food or nutrients than the body needs leads to increased fat accumulation in the body. This increased fat accumulation is harmful and can lead to the production of toxic lipid metabolites. Some of the most harmful toxic lipid metabolites produced under conditions of excess nutrition are called ceramides. Ceramides have been linked to the development of various heart diseases and cancers. We have found a new protein in the body that we believe is controlled by ceramides and it is called Bone Morphogenetic Protein 3 (Bmp3). Bmp3 is significantly reduced in fat tissues when we inhibit ceramides, and it is significantly elevated with the increase in ceramides. With these findings, we are confident in our identification of Bmp3 as a ceramide-regulated transcript. In this study, we plan to better understand the role of Bmp3 in obesity and insulin resistance.
- Academic Unit
- Health and Human Physiology
- Record Identifier
- 9984647256802771
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