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Internal affairs in the Metabolic Phenotyping Core

Phenotyping Core lab

In 2006, Dr. Joel K. Elmquist and the late Dr. Alfred G. Gilman – then Dean of UT Southwestern Medical School – were kicking around ideas for metabolic research facilities at UT Southwestern.

Drs. Joel Elmquist, Chen Liu, Syann Lee, Caleb Lord
(l-r) Drs. Joel Elmquist, Chen Liu, Syann Lee, Caleb Lord

Dr. Elmquist proposed a facility to study mouse metabolic traits (phenotypes) under tightly controlled conditions. The Professor of Internal Medicine, Pharmacology, and Psychiatry suggested a 24-cage facility.

“Dr. Gilman said, ‘Nope, you aren’t getting 24 cages. You’re getting 36, but you’re turning it into a Core facility.’ It became the largest one in the country at the time,” Dr. Elmquist recalls. “Now, there’s not a study that comes out of the Center for Hypothalamic Research or the Touchstone Center for Diabetes Research that doesn’t use the Core.” The Metabolic Phenotyping Core (MPC), overseen by Dr. Philipp Scherer, Dr. Elmquist, and Dr. Jay Horton, is in the Touchstone Center.

UT Southwestern is especially strong in metabolic research, Dr. Elmquist says, and as a result it’s one of the best places in the world to conduct science in this area. “Much of the work uses genetically modified mice, and you have to perform in-depth metabolic phenotyping to understand what a gene or protein is doing.”

Dr. Alfred G. Gilman
Dr. Alfred G. Gilman

He credits Dr. Gilman – the 1994 Nobel Laureate in Physiology or Medicine – for his foresight. The Core provides many benefits, including the ability to offer a range of techniques to investigators, to standardize data collection, and to speed research on metabolic disorders. Although the facility has changed a lot over the years, its webpage remains the best way to access capabilities and price lists.

Gilman’s vision

The MPC can collect data on mouse food and water intake, metabolic rate, energy expenditure, and body heat production. The specialized chambers for these measurements are climate-controlled, which facilitates studies of thermogenic brown and beige fat. Director Dr. Ruth Gordillo and Co-Director Dr. Syann Lee, both Assistant Professors of Internal Medicine, are in charge of the facility’s day-to-day operations.

The newest additions to the facility include an XYZ laser beam system – lasers that send beams in all three dimensions to track an animal’s movement.

Dr. Ruth Gordillo
Dr. Ruth Gordillo, MPC Director

“When an animal moves around the cage, a beam breaks. That tells us how much the mouse moves, whether it is on its hind legs, and how often the animal is at the feeder. You can get data to answer questions such as ‘Are they eating more frequently? Eating for longer periods of time?’ You can get detailed information about eating behaviors,” says Dr. Elmquist, a veterinarian and Director of the Center for Hypothalamic Research at UTSW.

The Core offers insulin and glucose clamp studies on rodents so that researchers can assess glucose production and uptake by different tissues as well as insulin action in specific parts of the body. 

Playing to competencies

Located nearby in the same building is one of the newest, largest collaborative spaces on campus. Although not a core facility, the newly renovated 2,000-square-foot Center for Human Nutrition mass spectrometry laboratory is a gathering spot for a dynamic collection of instruments used by researchers in Biochemistry, Molecular Genetics, Pharmacology, and the Touchstone Center.

(l-r) Dr. Goncalo Dias do Vale, Dr. Jeff McDonald, and Bonne Thompson
(l-r) Dr. Goncalo Dias do Vale, Dr. Jeff McDonald, and Bonne Thompson in the mass spectrometry laboratory.

Dr. Jeff McDonald, Associate Professor in the Center for Human Nutrition with a secondary appointment in Molecular Genetics, led the design of the Center’s mass spectrometry laboratory, which is quickly becoming a hub for metabolomics, lipidomics, and fluxomics (the study of metabolite changes over time).

Metabolomics allows researchers to look inside cells to study the effects of drugs or disease states on the metabolites that are key to cellular function.

“The shared mass spectrometry lab is definitely unique on campus. Bringing most of the instruments out of individual labs in different departments and putting them into a common space builds a collaborative, stimulating research environment,” says Dr. McDonald, who runs a similar laboratory that specializes in lipids in the Center for Human Nutrition.

The MPC also has instruments in the shared space for fee-for-service mass spectrometry-based analyses. For more information, contact Dr. Gordillo.

Dr. Margaret Phillips
Dr. Margaret Phillips

Biochemistry Chair Dr. Margaret Phillips, Professor of Biochemistry and Pharmacology, says her Department moved several instruments into the mass spectrometry laboratory and shares excess capacity with researchers outside the Department.

“One instrument allows us to assess levels of metabolites in a sample from a range of about 150 soluble ones that the instrument has been trained to recognize, such as amino acids. The lipid mass spectrometry lab that Dr. McDonald runs in the Center for Human Nutrition has the ability to measure nonsoluble lipids and their metabolites, so between us we have a range of capabilities,” Dr. Phillips says.

“We also have an exact mass instrument, a form of mass spectrometry that allows biochemists to perform untargeted metabolomics, chemists to confirm the identity of compounds they synthesize, and pharmacologists to study how drugs are metabolized,” she says.

Sensitivity and speed

Dr. McDonald says the biggest improvements in mass spectrometry over the last 10 years have come in sensitivity – the ability to detect lower and lower levels of lipids such as triglycerides, phospholipids, and sphingolipids – as well as the speed with which one can make the measurements. Advances include moving into stable, nonradioactive labeling based on deuterium (heavy water), which is safer, more specific, and less expensive than tritium and could ultimately lead to measurements taken directly on patients.

“Now we are developing techniques to measure flux and changes in lipids in ways that have never been done before.”

Dr. Jeff McDonald

Dr. Matthew Mitsche, Assistant Professor in the Center for Human Nutrition and of Molecular Genetics, is the primary driver behind advanced flux workflows using ultrahigh resolution techniques. A former postdoctoral researcher in the Hobbs/Cohen laboratory, Dr. Mitsche has a background in chemical engineering, biophysics, lipid physiology, and mass spectrometry that makes him uniquely qualified to pursue this line of research, Dr. McDonald says.

“The lipid mass spectrometry lab provides collaborative resources for researchers in the Center for Human Nutrition and also in the UTSW community to do lipidomics research studying how lipids function in biological models,” he says.

“Now we are developing techniques to measure flux and changes in lipids in ways that have never been done before. We are doing these flux experiments in cell and mouse models today,” Dr. McDonald says. “And we are adding another instrument that will increase our capabilities to measure flux in simple lipids in complex experiments in animals and potentially humans.”

Dr. Elmquist holds the Carl H. Westcott Distinguished Chair in Medical Research and the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr. Roy A. Brinkley.

Dr. Horton is Director of the Center for Human Nutrition and Professor of Internal Medicine and Molecular Genetics. He holds the Distinguished Chair in Human Nutrition, the Center for Human Nutrition Director’s Endowed Chair, the Scott Grundy Director’s Chair, and The Dr. Robert C. and Veronica Atkins Chair in Obesity & Diabetes Research.

Dr. Phillips holds The Sam G. Winstead and F. Andrew Bell Distinguished Chair in Biochemistry.

Dr. Scherer is Director of the Touchstone Center for Diabetes Research and Professor of Internal Medicine and Cell Biology. He holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research.