Dr. John Newman is an avid collaborator with researchers in the WHNRC, the U.S., and abroad who brings expertise in analytical biochemistry, state-of-the-art analytical instrumentation and the use of metabolomics to the WHNRC. Dr. Newman is applying these tools to determine the impact of diet and dietary components on human health, with a special emphasis given to the obesity problem, its complications associated with the high fat "Western" diet and the variability in individual responses to dietary factors.
Dr. Newman is a California native who has received higher education in Colorado and California. He obtained a baccalaureate degree in biochemistry and molecular biology from the University of California Santa Cruz in 1991, worked extensively in the field of environmental analytical chemistry until 1996, obtained a Ph.D. in pharmacology and toxicology from the University of California, Davis in 2002, and worked as a Research Associate at UC Davis until 2005 exploring the biomedical applications of eicosanoid metabolic profiling. He has extensive experience in trace organic quantitative chemistry, data quality assessment and quality control, analytical method development, as well as modest skills in chemical synthesis and technical experience with a range of state-of-the-art analytical instrumentation: NMR spectroscopy (1H, 13C, 15N, 19F); gas and liquid chromatographic systems (GC, GPC/SEC, FPLC, GPLC, UPLC); gel electrophoresis; mass spectroscopy (MALDI-TOF-MS, API-TOF-MS, API-MS, API/MS/MS). He has applied spectroscopic analysis to support structural confirmation of synthetic products, structural elucidation of unknown products, identification of protein modification, and quantitation of both exogenous and endogenous molecules isolated from an array of biological matrices. Dr. Newman has focused these efforts on the development and application of analytical tools to profile a broad range of lipids with important roles in the regulation of inflammation, vascular and renal function, and cellular growth.
Investigations surrounding the endogenous role of the soluble epoxide hydrolase were at the root of these investigations. They have since expanded to encompass products of the major lipid oxygenases including prostanoids and various eicosanoids as well as analogous materials generated for eighteen and twenty-two carbon lipids. These analytical profiling efforts have more recently broadened to investigate other bioactive lipid mediators involved in the regulation of energy balance and body mass, including a suite of endocannabinoids. The role of these regulatory pathways have been explored in inflammation, renal function, vascular regulation and disease, blood pressure regulation and both male and female reproductive physiology. More recently, these tools have been turned on the lipoprotein particle, and subtle structural changes in these particles are beginning to be observed.
During his research career, Dr. Newman has written or supported more than 60 articles in peer-reviewed journals. He has served as a peer reviewer for an array of journals including the American Journal of Clinical Nutrition, the British Journal of Nutrition, the Journal of Chromatography, Archives in Biochemistry and Biophysics, Chemosphere, Proteomics, and Metabolomics. In addition, Dr. Newman is a member in good standing in the Metabolomics Society and the American Chemical Society.
The Newman laboratory research program is investigating the impact of dietary lipids on process associated with obesity and inflammation, how these effects alter the structure and function of lipoprotein particles, and how these cumulative changes produce coordinated changes in tissue lipid metabolism and signaling. At the heart of this research is an effort to understand whether fine-tuning an individual's dietary lipid intake can improve body weight and health beyond those recommended to the general population by the U.S. Dietary Guidelines. To achieve these goals, the group combines high information content analytical chemistry with biochemistry, human interventions, as well as cell and molecular biology to investigate the impact of dietary lipid content and composition on PPAR-dependent signaling, inflammatory status, adipocyte growth and differentiation, and changes in systemic eicosanoid and endocannabinoid system tones. These research goals promise to extend and complement the WHNRC's impact in the area of dietary fats on health outcomes accomplished by previous ARS scientists Drs. Iacono, Nelson, Kelly and Hwang over the past 40 years.
Specific Research Areas
Do lipoprotein particles deliver bioactive lipids to peripheral tissues? A central hypothesis being tested in the laboratory is that lipoprotein particles transport bioactive signaling lipids to peripheral tissues, influencing homeostatic set points, and that this process is influenced by dietary lipid compositions. With the exception of small free fatty acid and lyso-phosphotide pools associated with albumin, plasma lipids are esterified within lipoproteins, where apolipoproteins facilitate systemic lipid trafficking. Moreover, the dietary saturated/monounsaturated/polyunsaturated fatty acid balance has significant impacts on the structure and function of lipoprotein particles and lipid trafficking, with consequences on vascular health. For instance, high omega-3 fatty acid consumption can have both anti-inflammatory and anti-hypertriglyceridemic cardioprotective effects. In obese animals, high n3 LC-PUFA diets can also reduce weight and hypothalamic drivers of hunger, while increasing anorexigenic adipokine production, and improve central sensitivity to these adipokines. While LpL-mediated lipolysis dominates VLDL clearance, whole particle uptake of VLDL1 accounts for 20-30% of clearance in normolipidemic humans, and dominates LDL and HDL clearance. Moreover, fish oil feeding increases adipose expression of the oxo-LDL receptor CD36 through the PPAR-? dependent mechanisms. Since cell growth and differentiation is influenced by PUFA metabolites, including eicosanoids and endocannabinoids produced within cells, delivery of these agents preformed to cells could have profound effects on cellular homeostasis. Our earlier studies have shown that obesity increases concentrations of oxygenated lipids esterified into lipoprotein particles, that these lipids are released by lipoprotein lipase, and their release is associated with a postprandial inflammatory response in the vascular endothelium. In addition, we have seen that n3 LC-PUFA supplementation significantly alters the profiles of circulating oxygenated PUFAs. Current efforts in the laboratory are designed to evaluate the ramifications of these altered lipoprotein structures on the function of exposed cellular systems including vascular and adipose cell types.
Does variance in LC-PUFA biosynthesis influence the efficacy of dietary fish oil? Dietary PUFAs in the United States are rich in linoleic (LA; 18:2n6) and alpha-linolenic (ALA; 18:3n3) acids, essential fatty acid precursors to the long chain (i.e. ? twenty carbon) n6 and n3 PUFAs (LC-PUFAs). LC-PUFA biosynthesis greatly outweighs their dietary intake in most individuals, but these rates vary, being influenced by lipid consumption, gender, and genetic polymorphisms. How LC-PUFA biosynthetic efficiency impacts the beneficial effects of n3 LC-PUFA consumption is not known, but responses to fish oil feeding also vary. We hypothesize that those individuals with reduced LC PUFA biosynthetic capacity may be more sensitive to the therapeutic effects of a high fish oil diet and are testing this hypothesis with both retrospective and prospective studies. To approach these questions, we are investigating product:substrate ratios of metabolic intermediates as indices of LC-PUFA biosynthesis in human, focusing on markers of elongase activity (i.e. 22:5n3/20:5n3 + 22:6n6/20:4n6) in red blood cell phospholipids. We have found that these markers increase as the LC?PUFA n6/n3 ratio increases (n=768; p<0.0001), findings consistent with reports that high n6 PUFA diets inhibit the conversion of 18:3n3 to 20:5n3. However, on inspection of other product:substrate ratios, apparent differences in LC?PUFA handling are seen. In particular, the variance in elongase (ELO) activity increases as the n6:n3 ratio increases. Also, the frequency distributions of the LC-PUFA n6/n3, LC?ELO index and a delta-5 desaturase (D5D) index are all bimodal yet unique. Current efforts in the lab are focused on understanding the interactions between these metabolic phenotypes and individual responses to fish oil interventions.
Selected Publications & Patent Applications