Why being overweight makes (SOME) people sick

Not everyone who gains weight develops insulin resistance and metabolic disease. Can research reveal why?

Tracey McLaughlin, MD

Most Americans today have a body mass index (BMI) that, by definition, puts them somewhere in the range of overweight to obese. But those on the upper end of the BMI spectrum aren’t always the least healthy, even when it comes to diseases linked to weight. Someone whose BMI is barely in the “overweight” range may be plagued with diabetes, heart disease, fatty liver, and high blood pressure, while an obese individual may be metabolically healthy. It’s a conundrum that’s puzzled doctors in recent decades, even as the waistline of the average American has grown.

“We still don’t know what causes some people to get insulin resistance when they gain weight, while others seem to be protected,” says Tracey McLaughlin, MD, an associate professor in the Division of Endocrinology. But McLaughlin is on the hunt to find out.

She and Michael Snyder, PhD, a professor of genetics, received a $3.2 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). Their plan is to survey the molecular signatures of blood and fat cells in overweight and obese individuals in whom insulin resistance will be induced and then reversed by, respectively, dietary weight gain and loss.

Researchers know that, in general, insulin resistance—the first sign that the body isn’t processing blood glucose correctly—is linked to weight gain. In turn, insulin resistance can lead to prediabetes and type 2 diabetes, as well as high triglycerides, hypertension, heart disease, stroke, fatty liver disease, and many cancers. Weight loss, in most cases, reverses insulin resistance and prevents the development of metabolic syndrome and associated clinical morbidities.

During the past 10 years McLaughlin has been working out some of the details that make some overweight people more prone to insulin resistance than others. “It has to do more with the qualitative aspects of fat than the quantitative aspects,” she says.

McLaughlin has completed both metabolic phenotyping and radiologic measures of where fat is stored. She has also performed fat biopsies on over 600 human subjects. And she performed further research with Samuel W. Cushman, PhD, of the NIDDKD.

Based on that work, McLaughlin and Snyder now want to do even more in-depth studies of fat and blood from overweight and obese individuals who are subjected to a weight-challenge intervention. One goal is to find a biomolecular signature that can help tell clinicians which people are insulin resistant and at risk of developing metabolic syndrome; another goal is to find molecular pathways that link excess body fat to insulin resistance.

“Not all overweight and obese people are metabolically unhealthy. Only about half of them have insulin resistance, and the obesity-related health consequences are concentrated in this group,” says McLaughlin. “So it’s important to try to figure out who’s at risk for those diseases and focus resources on keeping them from gaining weight.”

Furthermore, she says, identifying the molecular pathways that link weight gain and insulin resistance may lead to new drugs.

As part of their studies, the researchers are taking blood, fat, and stool samples as participants gain and lose weight to study how levels of different molecules—from RNA to proteins, along with immune cells and the microbiome—change during weight perturbations. They’ve already collected data on 66 people and are recruiting more individuals toward their goal of 100 people for the study.

“Once we can identify people in this very early disease state, the first intervention is very easy and cost effective—it’s lifestyle changes,” McLaughlin points out.