Hao-Wei Chang, Ph.D.

ABSTRACT

Obesity is usually accompanied by insulin resistance, dyslipidemia, prediabetes or type 2 diabetes, and fatty liver disease — but a subset of people with obesity, nearly all of them women, are resistant to these effects and are considered to have “metabolically healthy obesity” (MHO). The protective mechanism is largely unknown. One candidate is adipose tissue capillarization: people with MHO show higher adipose tissue oxygenation and lower inflammation, and in mice, boosting blood vessel density protects against diet-induced metabolic dysfunction. Healthy vessel networks depend on macrophages, and the PI’s prior work identified a CD206+ Lyve1+ macrophage subset that produces both pro- and anti-angiogenic factors, with net anti-angiogenic function in female mice. This project tests the hypothesis that macrophage function regulates adipose blood vessel density in human obesity. Aim 1 applies single-nucleus RNA sequencing to 36 banked subcutaneous adipose samples (18 MHO, 18 metabolically unhealthy) using on-chip multiplexing — an effort that would constitute the largest snRNA-seq atlas of human adipose tissue with complete donor metabolic-health phenotyping. Aim 2 uses whole-mount immunofluorescence to quantify vascular density and map TIMP3-expressing macrophages relative to blood vessels and crown-like structures. The resulting datasets will support planned K01, R21, and R01 applications.
Lay Summary:
Not everyone with obesity develops the health problems usually associated with it. A subset of people — almost all of them women — carry excess body fat without developing insulin resistance, diabetes, or fatty liver disease. Understanding what protects them could point toward treatments that break the link between obesity and metabolic disease for everyone else.
One clue is oxygen. Fat tissue in metabolically healthy individuals appears better oxygenated, which suggests it may be better supplied with blood vessels. Building and maintaining those vessels depends on immune cells called macrophages, and Dr. Chang’s earlier work in mice found a specific type of macrophage that can either encourage or suppress blood vessel growth. This project examines banked fat tissue samples from people with metabolically healthy and unhealthy obesity, reading the genetic activity of individual cells to compare their macrophages and blood vessel cells, and using imaging to directly measure how dense the blood vessel networks are. The result will be one of the most detailed maps yet of human fat tissue, and a clearer picture of why some people are protected from the consequences of obesity.