Paul A. Harding

Biographical Information

Obesity is the accumulation of white adipose tissue (WAT) which is involved in energy storage.  Another type of adipose tissue is brown adipose tissue (BAT) which is involved in heat generation and increased energy expenditure.  The primary focus of our lab is to understand the role of heparin-binding EGF-like growth factor (HB-EGF) in cellular reprogramming of cells into a BAT-like phenotype.  BAT is a type of fat that is involved in stimulation of non-shivering thermogenesis resulting in generation of heat rather than ATP production.  BAT is characterized by having an increased number of mitochondria as well as expressing PR domain 16 (PRDM16) transcriptional co-regulator, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a) and uncoupling protein 1 (UCP-1).

HB-EGF undergoes proteolytic processing by a disintegrase and metalloprotease (ADAM) 12S, an enzyme that processes HB-EGF yielding both soluble and intracellular domains.  The soluble form of HB-EGF binds to and activates EGF receptors (EGFRs) resulting in stimulation of cell division, while the intracellular domain migrates to the nucleus and relieves transcriptional repressors involved in cell division.  Co-expression of HB-EGF and ADAM 12S results in lipid accumulation, increased mitochondrial staining, up-regulation of BAT genes (PRDM16, PGC-1a, UCP-1) and down-regulation of WAT genes, including CAAT-enhancer-binding protein (C/EBPa) and lamin A/C (LMNA) further supporting the hypothesis that HB-EGF/ADAM 12S co-expression reprograms cells to a BAT-like state.

Currently, an adenoviral gene-delivery system for HB-EGF and ADAM 12S is being characterized in order to demonstrate BAT-like cellular reprogramming of human adipose tissue collected form liposuction patients.  We hypothesize that HB-EGF/ADAM 12S co-expression reprogramms cells to a stem-like state mediated by fibroblast growth factor 2 (FGF2) and Krüppel-like factor 3 (Klf3) and results in BAT-like cells by induction of BAT genes and down-regulation of WAT genes. Experiments are being planned to investigate BAT cellular reprogramming in vivo.  Our research has possible therapeutic applications to combat obesity and type 2 diabetes.

Selected Publications

• Cartwright KM, Sferrella A, Long EC, and Harding PA. Cellular reprogramming of human primary adipocytes into metabolically active brown adipose-like cells. In preparation.
• Duan, E, Zhou Z, and Harding PA (2019) Lack of HB-EGF is protective against streptozotocin-induced renal disease. Growth Factors, under review.
• Taylor SR, Gemma, CA, Cartwright KM, Pfeil DC, Miller ER, Long EC, and Harding PA (2018) HB-EGF and ADAM 12S directed cellular reprograming results in metabolically active brown adipose tissue-like cells. Cell and Tissue Engineering 2(4) 203-219.
• Taylor SR, Markesbery MG, and Harding PA (2014) Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and proteolytic processing by a disintegrin and metalloproteinases (ADAM): a regulator of several pathways. Seminars in Cell Developmental Biology 28: 22-30.
• Zhou Z, Darwal MA, Cheng EA, Taylor SR, Duan E, and Harding PA (2013) Cellular reprogramming into brown adipose-like phenotype by co-expression of HB-EGF and ADAM 12S. Growth Factors, 31(6): 185-198.

Courses Taught

• Biological Concepts: Structure, Function, Cellular, and Molecular Biology (BIO 116)
• Human Physiology (BIO 161)
• Human Heredity (BIO 232)
• Genetics (BIO 342)
• Molecular Techniques (BIO 464)
• Applications of Biotechnology to Human Health: Concepts and Issues (BSC 416)