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    Mayo Clinic, Rochester, Minnesota

Causes and consequences of differences in body fat distribution

General Research Subject: Obesity

Focus: Adipocytes, Integrated Physiology\Fatty Acid Metabolism, Obesity\Pathogenesis

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2012

Project End Date: June 30, 2016

Diabetes Type: Type 2 diabetes

Research Description

 This Mentor-Based Postdoctoral Fellowship Award will support the training of a qualified Ph.D. in the field of metabolic research with respect to obesity, metabolic syndrome and Type 2 Diabetes. The research fellow will learn: 1) How to use unique, detectable fat molecules to measure how the body's fat cells take up and store fat; 2) How to use state-of-the-art instruments that can measure stable isotopes of fat-containing molecules; 3) The bench laboratory assays needed to measure fatty acid storage factors in fat cells collected from research volunteers; 4) How to perform adipose (and muscle) biopsies in a safe, supervised environment.

The trainee will gain these skills in the context of conducting an NIH-funded study involving volunteers with various conditions that selectively affect different fatty acid storage proteins. Examples include men with low levels of male hormones (testosterone), who have high levels of some fat storage proteins in thigh fat, estrogen deficient women, who have high levels of a different fat storage protein in thigh fat, upper body obese women who have low levels of a third fat storage protein. The ability of fat cells to take up and store fat under conditions of high and low fat availability will be measured. This will help us understand the beneficial and potentially harmful ways that fat molecules can be handled by fat cells. It is anticipated that this fellowship will prepare a promising new Ph.D. as a successful independent investigator in the field of diabetes and metabolism.

 Research Profile

Mentor: Michael D. Jensen, MD       Postdoctoral Fellow: Kathleen Gavin, PhD

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

My research focus is to understand the interactions between adipose tissue and lean tissue as it relates to insulin resistance and predisposition to Type 2 Diabetes. Humans with excess upper body/visceral fat relative to lower body fat are more insulin resistant and have abnormal regulation of free fatty acid release from adipose tissue lipolysis. Previous studies have shown that experimental raising of FFA in lean, healthy persons can create insulin resistance. Thus, the focus of my research is to: 1) understand why some persons gain weight in the lower body and remain healthy despite "excess" body fat whereas others gain weight in the upper body/visceral fat regions; 2) what are the fates of FFA once released from adipose tissue? – What tissues are disproportionately affected by elevated FFA? How are fatty acids trafficked within tissues? Are their regulatory steps – uptake, esterification, triglyceride synthesis – that protect or fail to protect some tissues in some persons from insulin resistance? Our laboratory uses a combination of methods to address these issues, ranging from dynamic [11C]palmitate PET/CT studies to identify which tissues preferentially take up FFA to stable isotope/biopsy studies to understand how adipose, muscle and liver handle FFA in either favorable or unfavorable manners depending upon the predisposition to Type 2 Diabetes and their nutritional status.

We have developed a number of novel approaches that allow us to measure both the rates of fatty acid trafficking within cells/tissues combined with measures of the proteins and enzymes that may be rate limiting in the synthesis of compounds that may contribute to insulin resistance (ceramides, diacylglycerols). In this way we intend to identify why some individuals are protected from the metabolic consequences of obesity whereas others are not.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Some people develop diabetes when they gain excess weight and others do not. Until we find a way to prevent weight gain altogether, I believe the next best approach is to learn why some people are protected from developing diabetes even when they gain weight. If we can recapitulate the mechanisms that prevent diabetes learned from the study of obese persons who are not predisposed to diabetes I believe we can develop treatments to treat/prevent diabetes that are virtually risk free.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

I have been investigating the role of obesity in the predisposition to Type 2 Diabetes for almost 25 years. Unfortunately, even though we have learned a great deal about how obesity predisposes to diabetes, the prevalence of obesity has also increased in the United States during that time. As a clinician I see a large number of patients with obesity and Type 2 Diabetes for whom our current approaches are suboptimal. Fortunately, this experience drives some of the research questions we ask and I believe this makes our investigations more relevant to directly addressing patient care issues.

In what direction do you see the future of diabetes research going?

For Type 2 diabetes the important research questions are: 1) What are the main causes of insulin resistance and how do we reverse/prevent it? 2) Why do the islet cells eventually fail to produce insulin and what can be done to prevent this? To address the first question we will need to understand the relative contributions of lipotoxicity and cytokines/adipokines at the level of multiple tissues – muscle, liver and even adipose tissue itself.

The former question is more readily address in clinical/human studies because gaining access to muscle, liver and fat is easier and safer than collecting pancreatic tissue from humans. I believe the ability to perform sophisticate studies with human research volunteers is key to making the final translation of findings in experimental animals. In addition, there is really no good animal model for the striking differences in body fat distribution we see in humans. To the extent that body fat distribution is an important predictor of Type 2 Diabetes and insulin resistance, understanding this relationship at a cellular and molecular level is very important.