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Amnon Schlegel

Assistant Professor of Internal Medicine and Adjunt Professor of Biochemistry

B.S. Hofstra University

M.D. Albert Einstein College of Medicine

Ph.D. Albert Einstein College of Medicine

Research

References

amnons@u2m2.utah.edu

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Research

Pandemic obesity brought on by social and economic factors beyond the control of individuals threatens to negate the gains made in global health over the past century. The improvement in duration and quality of life achieved by greater sanitation, safer obstetric care, vaccination against endemic viral and bacterial diseases, and management of chronic conditions like hypertension and dyslipidemia may be undermined by obesity. Because it is unclear if the prevalence of obesity has reached a plateau stage or will continue to expand, many more persons may be at risk for obesity-related morbidity and mortality. This expanded pool of humans has few therapeutic options because we have limited ability to reverse the social and economic forces that drive obesity, and we suffer from a lack of knowledge of the way energy homeostasis is maintained.

Using a zebrafish genetic approach, several complex human phenotypes have been studied in detail. Because it has the conventional vertebrate body plan that includes central and peripheral nervous systems, a multi-organ digestive system, and adipose tissue,  zebrafish is well suited for studies modeling human energy metabolism. Zebrafish embryos and early larvae are metabolically active, transporting neutral lipids from the maternally supplied yolk to the growing tissues until the yolk is exhausted by 5 days post-fertilization (dpf), when feeding begins. In background work, we found that these events can be monitored in situ with conventional stains of neutral lipids (Schlegel and Stainier, 2006). Furthermore, targeted knockdown of evolutionarily central genes involved in lipid transport (microsomal triglyceride transfer protein, mtp)in zebrafish larvae recapitulates the phenotypes observed in mice with targeted inactivation of the orthologous gene Mtp and in humans bearing disease-causing mutations of the ortholog MTTP.

Based on these preliminary studies and our optimization of several biochemical and imaging assays, we seek to establish a zebrafish molecular genetic system for identifying novel genes and potential therapeutic targets that give rise to obesity and obesity-related phenotypes. The approach taken is a large-scale, unbiased, forward genetic screen for mutations that cause said phenotypes in zebrafish larvae, followed by positional cloning and detailed, mechanistic characterization of the mutated genes’ functions.

Of the obesity-related disease processes just mentioned, it is important to underscore that excessive liver accumulation of lipids (hepatic steatosis) is present in a large fraction of obese persons and is associated with insulin resistance. Alarmingly, hepatic steatosis is found in 30% of the general population, is present in nearly two-thirds of patients with diabetes mellitus, and is seen in over 90% of very obese persons seeking weight-reduction surgery. Nonalcoholic fatty liver disease (NAFLD) encompasses hepatic steatosis and several pathological states that follow it: inflammation (steatohepatitis), fibrosis (cirrhosis) and cancer (hepatocellular carcinoma). This vague name stresses the heterogeneity in clinical and pathological findings. There are limited therapeutic options for permanently ameliorating hepatic steatosis and there are no methods for reversing hepatic fibrosis, or preventing hepatocellular carcinoma due to NAFLD. Thus, very high direct and indirect health costs are sustained by inappropriate accumulation of neutral lipids in the liver.

The inability to treat NAFLD reflects a lack of detailed knowledge of what triggers it. The first step of NAFLD is the inappropriate accumulation of triacylglycerol in the hepatocyte  This accumulation may be due to excessive de novo hepatic lipid production, decreased hepatic secretion of very low density lipoprotein particles, diminished beta-oxidation of fatty acids in the liver, more subtle defects in regulating energy homeostasis including insulin resistance or central nervous system nutrient sensing, or a combination of these factors. Since each of these steps could be amenable to therapeutic exploitation, understanding their regulation is paramount.

Along similar lines, we are interested in identifying mutants with alterations in adipose lipid mass. Using the same strategy for identifying mutants with hepatic steatosis mutants, we are identifying mutants with expanded adipose lipid mass (operationally called “obese”), and decreased adipose lipid mass (“lipodystrophy”). Given my background as a cell biologist, it is important to stress that positional cloning of  mutated genes represents a starting point for our invstigations: we seek mechanistic answers to why mutations give rise to complex physiologic changes.

Interest Groups:Metabolism Interest Group, Zebrafish Interest Group and Membrane Biology Interest Group.

References