Dorfman Laboratory

Exploring the protective role of sex steroids in hypothalamic inflammation, obesity, and cardiometabolic disease

Obesity is a global epidemic and a major public health concern because it greatly increases the risk of type 2 diabetes (T2D), hypertension, cardiovascular disease, and many cancers. A growing body of research shows that these metabolic disorders are often linked to hypogonadism (low levels of sex hormones — testosterone in men and estradiol in women), a reproductive disorder that significantly elevates metabolic risk. The biological mechanisms connecting reproductive function and metabolism remain poorly understood, but emerging evidence points to a key role for hypothalamic gliosis (inflammation of brain support cells called glia).

Work from our group and others has shown that the brain is central to the regulation of energy balance by coordinating food intake (energy in) and energy expenditure (energy out). The hypothalamus, in particular, acts as a hub where neurons and glial cells sense hormones and nutrients to maintain metabolic stability. We previously demonstrated that consumption of a high-fat diet (HFD) activates glial cells (astrocytes and microglia) in the hypothalamus of rodents, and human studies support these findings by showing a positive correlation between hypothalamic gliosis and body mass index (BMI) as well as a negative correlation between gliosis and testosterone levels. Importantly, we recently found that hypogonadism and HFD act synergistically to trigger hypothalamic inflammation before the onset of obesity, glucose intolerance, and other cardiometabolic risks.

Building on these discoveries, the Dorfman Lab is pursuing several projects to advance our understanding of brain–hormone–metabolism interactions:

1. Defining the role of glial estrogen and androgen receptor signaling in diet-induced obesity and cardiovascular disease.
2. Identifying central and peripheral molecular mechanisms by which hypogonadism predisposes to metabolic disease.
3. Investigating how hypothalamic gliosis induced by a high-fat diet affects reproductive function.

Ultimately, our work aims to uncover how sex steroids protect against obesity, diabetes, and cardiometabolic disease, with the long-term goal of identifying new strategies to improve health in both men and women.