Project: Adipose Tissue Biology and Effect of Weight Loss in Women with Lipedema

Principal Investigator: Samuel Klein, MD
Co-Prinicipal Investigator: Vincenza Cifarelli, PhD
Washington University School of Medicine
Center for Human Nutrition
St. Louis, MO

Summary

The purpose of this proposal is to conduct a comprehensive characterization of body fat distribution (assessed by dual-energy x-ray absorptiometry and magnetic resonance imaging), insulin sensitivity (assessed by using the hyperinsulinemic-euglycemic clamp procedure), and adipose tissue biology (immune cell content by flow cytometry and gene expression of key metabolic pathways by RNA sequencing) in lean and obese women with Lipedema and women matched on total body fat but without Lipedema before and after 8%-10% diet-induced weight loss.

Background

Little is known about the alterations in adipose tissue (AT) biology and systemic metabolic physiology associated with Lipedema. Immune cell profiles in both femoral and abdominal AT, systemic inflammation and careful assessment of insulin sensitivity have not been evaluated. Although diet-induced weight loss is the cornerstone of therapy for people with obesity, liposuction is currently the standard treatment in Lipedema because it is believed that diet-induced weight loss does not decrease lower-body fat mass in this patient population. We are not aware of any studies that have evaluated the effect of clinically significant (i.e., ~8%-10%) weight loss on body composition, AT biology and metabolic function in people with Lipedema. Our study will fill many important gaps in our knowledge of the basic biology of Lipedema and the response to 8%-10% weight loss. These data will provide a framework for future studies that can further explore the mechanisms and potential therapy for this patient population.

Methodology

In Aim 1, we will determine the effect of ~8%-10% weight loss on body composition in lean and obese women with Lipedema. Total body, upper-body and lower-body fat, intra-abdominal adipose tissue volumes, intrahepatic triglyceride content and thigh adipose tissue volume masses will be determined by using dual-energy x-ray absorptiometry (DXA, Lunar iDXA, GE Healthcare Lunar, Madison, WI) and magnetic resonance imaging (MRI, 3-T superconducting magnet; Siemens, Iselin, NJ). We hypothesize that calorie restriction-induced weight loss will reduce whole-body and leg-specific fat mass in women with Lipedema.

 In Aim 2, we will determine differences in insulin sensitivity in people with Lipedema compared with BMI matched controls and the effect of ~8%-10% weight loss on insulin sensitivity in women with Lipedema. Liver and skeletal muscle insulin sensitivity will be determined by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions.

 In Aim 3, we will determine the effect of Lipedema on adipose tissue biology (adipose tissue immune cell content and gene expression) and plasma markers of inflammation at baseline and after ~8%-10% weight loss. We will assess adipose tissue: i) stromal vascular fraction immune cells by using 11-color flow cytometry; and ii) gene expression of markers of inflammation, fibrosis, and blood/lymphatic vasculature in subcutaneous abdominal and femoral adipose tissue. Plasma cytokine concentrations will be also assessed before and after weight loss.

Expected outcomes

Our overarching hypotheses are that: 1) women with Lipedema have an increase in adipose tissue proinflammatory immune cells, markers of inflammation and fibrosis, but have greater insulin sensitivity than women matched on BMI without Lipedema; and 2) calorie restriction-induced weight loss will reduce whole-body and lower body (leg) fat mass to a similar extent compared with people without Lipedema and improve insulin sensitivity.

Practical implementations of results

This study will fill several important gaps in our knowledge of Lipedema in people with and without obesity by: i) providing a comprehensive whole-body, organ system and cellular metabolic and immune system characterization of people with Lipedema, and comparing these findings to BMI-matched control participants; and ii) determining whether people with Lipedema have the same adipose tissue remodeling and metabolic improvements typically associated with diet-induced weight loss in people without Lipedema.

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