2011 Post-Doc, University of California-Davis, Davis, CA,

Obesity, Diabetes, Cancer and Cardiovascular Diseases

2009 PhD, University of Quebec at Montreal, Montreal Canada,

Cancer

2004 MS, University of Quebec at Montreal, Montreal Canada,

Cancer

2001 BS, Faculty of Center, Monastir, Tunisia,

Reproductive Biology

Genetics, Nutrition, Metabolism and Cardiovascular Diseases.

The primary focus of research at the Bettaieb lab centers on the exploration and characterization of innovative strategies—whether dietary, pharmacological, or molecular genetics—to mitigate and prevent obesity, diabetes, and their related metabolic disorders. Our methodology involves leveraging dietary supplements to activate metabolic pathways akin to those induced by exercise and caloric restriction within the body. Through a combination of in vitro and in vivo methodologies, we systematically analyze the functionality and impact of crucial metabolic proteins and enzymes implicated in the development of obesity and diabetes. The overarching objective of our research is to unearth novel strategies for alleviating or treating these conditions, utilizing a spectrum of interventions, including pharmacological, genetic, and nutritional approaches.

To learn more about research at the Bettaieb, please watch this video.

Contribution to Science

1. Investigating the synergistic effects of Zyflamend and polyphenol-rich phytochemicals on adipogenesis and diet-induced obesity. Pharmacological and affordable approaches to combat the global epidemic of obesity have had limited success despite intensive efforts. To identify new targets and novel therapeutic approaches that could treat obesity, I recently characterized the anti-obesity potential of Zyflamend — a unique poly-herbal blend (PHB) with a well-defined combination of 10 phytochemicals, each of which is included at a low dose relative to single-use supplements. Using doses equivalent to those recommended by the manufacturer for humans, we found that oral administration of PHB provides resistance to high fat diet-induced obesity, glucose intolerance, and dyslipidemia in mice. These effects are accompanied by activation of the intracellular energy sensor Adenosine Monophosphate-Activated Protein Kinase (AMPK) and by evidence of browning in white adipose tissue. AMPK regulates the metabolic activity of brown and beige adipose tissue through several mechanisms including transcriptional regulation, stimulation of lipolysis, activation of the mTOR pathway, and modulation of ATP levels. In collaboration with investigators from Oak Ridge National Laboratory (ORNL), the University of Tennessee Institute of Agriculture (UTIA), and the University of Tennessee Medical Center (UTMC), we developed a multidisciplinary team to assess the molecular mechanisms underlying PHB’s anti-obesity potential, the molecular mechanism mediating its function, and the clinical significance of using PHB to treat and prevent obesity and its complications. We also investigated the anti-obesogenic effects of other phytochemicals including Shikonin and (-)-Epicatechin (see complete list of publication). Record of Invention – 2022 – Co-inventor on a Record of Invention submitted to the University of Tennessee, Knoxville. Title: “The Role of AICAR Transformylase in Obesity and Energy Expenditure”.
   471. Puckett D, Alquraishi M, Alani DS, Chahed S, Frankel VD, Donohoe D, Voy B, Whelan J, Bettaieb A. Zyflamend, a unique herbal blend, induces cell death and inhibits adipogenesis through the coordinated regulation of PKA and JNK. Adipocyte. 2020 Dec;9(1):454-471. PubMed Central PMCID: PMC7469463.
   472. Bettaieb A., et al. (2021) Zyflamend Supplementation Alleviates High-Fat Diet-Induced Obesity and Impairment of Skeletal Muscle Insulin Sensitivity. The FASEB Journal 35.
   473. Puckett D., et al. (2020) Zyflamend, a Unique Herbal Blend, Inhibits Adipogenesis Through the Coordinated Regulation of PKA and JNK. Current Developments in Nutrition 2019;4, 454.
   474. Record of Invention- 2022- Co-inventor on a Record of Invention submitted to the University of Tennessee, Knoxville. Title: “The Role of AICAR Transformylase in Obesity and Energy Expenditure”.

2. The metabolic functions of protein tyrosine phosphatases in obesity and metabolic homeostasis. My tenure at the University of California-Davis was very productive in advancing understanding of metabolic regulation. My research activities focused on addressing the metabolic and non-metabolic functions of protein tyrosine phosphatases, namely PTP1B, TCPTP and SHP2. Using combined genetic, biochemical, molecular, and mass spectroscopy approaches, I identified new physiological substrates for PTP1B in the adipose and pancreas tissues and provided new mechanistic and functional insights into the role of PTP1B in obesity, Type 2 diabetes, and acute pancreatitis. Similarly, I addressed the physiological role of hepatic Shp2 using liver-specific deletion. I demonstrated that liver-specific Shp2 deficient mice gained less weight and exhibited increased energy expenditure compared with controls. In addition, hepatic Shp2 deficiency led to decreased liver steatosis and prevented the development of insulin resistance following high fat feeding. These studies identified hepatic Shp2 as a novel regulator of systemic energy balance. I also investigated the endocrine and exocrine functions of TCPTP using pancreas-specific deletion, and showed that pancreatic TCPTP deficiency mitigated acute pancreatitis in mice and affected pancreatic beta cell function and insulin secretion.
   71. Bettaieb A, Bakke J, Nagata N, Matsuo K, Xi Y, Liu S, AbouBechara D, Melhem R, Stanhope K, Cummings B, Graham J, Bremer A, Zhang S, Lyssiotis CA, Zhang ZY, Cantley LC, Havel PJ, Haj FG. Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation. J Biol Chem. 2013 Jun 14;288(24):17360-71. PubMed Central PMCID: PMC3682537.
   72. Bettaieb A, Matsuo K, Matsuo I, Wang S, Melhem R, Koromilas AE, Haj FG. Protein tyrosine phosphatase 1B deficiency potentiates PERK/eIF2α signaling in brown adipocytes. PLoS One. 2012;7(4):e34412. PubMed Central PMCID: PMC3317973.
   73. Bettaieb A, Matsuo K, Matsuo I, Nagata N, Chahed S, Liu S, Haj FG. Adipose-specific deletion of Src homology phosphatase 2 does not significantly alter systemic glucose homeostasis. Metabolism. 2011 Aug;60(8):1193-201. PubMed Central PMCID: PMC4433310.
   74. Bettaieb A, Liu S, Xi Y, Nagata N, Matsuo K, Matsuo I, Chahed S, Bakke J, Keilhack H, Tiganis T, Haj FG. Differential regulation of endoplasmic reticulum stress by protein tyrosine phosphatase 1B and T cell protein tyrosine phosphatase. J Biol Chem. 2011 Mar 18;286(11):9225-35. PubMed Central PMCID: PMC3059022.
3. The role of soluble epoxide hydrolase in obesity, diabetes, and diabetic nephropathy. As an independent investigator and in collaboration with investigators from NIH, UC-Davis, the Medical College of Wisconsin, and the University of Cordoba Spain, I led several projects studying the metabolic and non-metabolic functions of soluble epoxide hydrolase (sEH). Using genetic, pharmacological, biochemical, and metabolomics approaches I identified sEH in glomerular podocyte as a significant contributor to renal function and diabetic nephropathy (DN). DN is one of the most devastating complications of diabetes and is the leading cause of end-stage kidney disease. Our recent findings on the topic are a paradigm shift in the history of DN because, until recently, injury of podocytes was considered a late consequence caused by increasing proteinuria rather than an event inciting the disease. We overturned this supposition by providing evidence that podocytes are functionally and structurally injured in the early stages of DN — suggesting that protection of podocytes will be of paramount importance in preventing DN development and progression. Equally important, these findings identified sEH in podocytes as a significant contributor to renal function under hyperglycemia, and may have translational implications for type 2 diabetes and kidney diseases. In a follow-up study, I discovered the role of sEH and endoplasmic reticulum (ER) stress in DN. Painful DN is one of the most challenging comorbidities of diabetes and a major contributor to hearing loss. The etiology and mechanisms of DN are complex and poorly understood despite intensive effort and improved understanding of the mechanisms responsible for progressive degeneration of nerve fibers. As a result, there has been limited success in developing therapeutic approaches. Together with Dr. Bora Inceoglu from the Hammock Laboratory at the University of California Davis, we demonstrated the causal role of ER stress and autophagy pathways in DN. This study was a breakthrough and a major advance in diabetes research. Not only did we uncover for the first time the molecular mechanisms of DN, but we also discovered a novel strategy to alleviate DN by modulating levels of epoxyeicosatrienoic acids (EETs). Our study was well received by the scientific community and recommended by F1000 Prime’s peer-nominated faculty. Frank Porreca, from the University of Arizona, called the main finding a “fabulous discovery” that reveals ER stress — which was only very recently linked to pain at all — as a potentially fundamental mechanism of pain regulation. “This really remarkable insight will surely lead to increased understanding of how neuronal hyperexcitability occurs” in neuropathic pain conditions. (Source: Stephani Sutherland on 24 Jul 2015).
   7582898. Overby H, Yang Y, Xu X, Graham K, Hildreth K, Choi S, Wan D, Morisseau C, Zeldin DC, Hammock BD, Wang S, Bettaieb A, Zhao L. Soluble Epoxide Hydrolase Inhibition by t-TUCB Promotes Brown Adipogenesis and Reduces Serum Triglycerides in Diet-Induced Obesity. Int J Mol Sci. 2020 Sep 24;21(19) PubMed Central PMCID: PMC7582898.
   7582899. Bettaieb A, Koike S, Hsu MF, Ito Y, Chahed S, Bachaalany S, Gruzdev A, Calvo-Rubio M, Lee KSS, Inceoglu B, Imig JD, Villalba JM, Zeldin DC, Hammock BD, Haj FG. Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia. Biochim Biophys Acta Gen Subj. 2017 Nov;1861(11 Pt A):2758-2765. PubMed Central PMCID: PMC5873293.
   7582900. Bettaieb A, Nagata N, AbouBechara D, Chahed S, Morisseau C, Hammock BD, Haj FG. Soluble epoxide hydrolase deficiency or inhibition attenuates diet-induced endoplasmic reticulum stress in liver and adipose tissue. J Biol Chem. 2013 May 17;288(20):14189-14199. PubMed Central PMCID: PMC3656275.
   7582901. Luria A, Bettaieb A, Xi Y, Shieh GJ, Liu HC, Inoue H, Tsai HJ, Imig JD, Haj FG, Hammock BD. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9038-43. PubMed Central PMCID: PMC3107315.
4. Polyphenol-rich phytochemicals and hyperthermia as non-invasive methods for treatment of cancer. The importance of dietary factors and caloric intake in modulating cancer risk has become increasingly apparent. Further efforts towards understanding the role of dietary factors in cancer biology, the metabolic and physiological consequences, and their associated clinical outcomes are needed. One area of research in my laboratory investigates the molecular mechanisms of cancer therapy using noninvasive methods such as hyperthermia and caloric restriction mimetics. For example, we recently investigated the effectiveness of Zyflamend as a Cox inhibitor for pancreatic and prostate cancer. We demonstrated that PHB has beneficial effects against pancreatic and prostate cancer, and that PHB can be used either as an adjuvant with medically-approved standard therapies or in a preventative manner. We also investigated the molecular mechanisms of hyperthermia as non-invasive treatment against multiple cancers including head and neck, breast, brain, bladder, cervix, rectum, lung, esophagus, liver, prostate, melanoma and sarcoma. We showed that hyperthermia could be used as a particularly effective complement to standard cancer treatments such as radiation therapy and chemotherapy.
   126. Puckett DL, Alquraishi M, Alani D, Chahed S, Donohoe D, Voy B, Whelan J, Bettaieb A. Zyflamend induces apoptosis in pancreatic cancer cells via modulation of the JNK pathway. Cell Commun Signal. 2020 Aug 14;18(1):126. PubMed Central PMCID: PMC7427957.
   127. MacDonald AF, Bettaieb A, Donohoe DR, Alani DS, Han A, Zhao Y, Whelan J. Concurrent regulation of LKB1 and CaMKK2 in the activation of AMPK in castrate-resistant prostate cancer by a well-defined polyherbal mixture with anticancer properties. BMC Complement Altern Med. 2018 Jun 18;18(1):188. PubMed Central PMCID: PMC6006779.

Complete List of Published Work in my NCBI or ORCID profile: (70 publications, ~3769 citations)

The full publication list for Dr. Bettaieb is available by searching “Bettaieb Ahmed” within Pubmed or by copying and pasting the following link:

https://www.ncbi.nlm.nih.gov/myncbi/16o7gUz8_0CQn/bibliography/public/