Active Grants — Metabolism and Molecular Nutrition Platform

Title: Defining the role of primary cilia in adipogenesis and obesity

Investigative team: Jinghua Hu, Ph.D., James L. Kirkland, M.D., Ph.D., Eduardo N. Chini, M.D., Ph.D.

Central hypothesis: The research team has identified a novel ciliary protein, FBF1, and discovered the essential role of FBF1 in regulating the function of cilia. In the current study, the team is investigating the molecular mechanism underlying how FBF1 acts in the context of cilia to regulate differentiation of cells into adipocytes (adipogenesis).

Primary cilia are present on most cell surfaces in the human body and are like antennas used by cells to sense the environment. Cilia dysfunctions contribute to a wide spectrum of human syndromic diseases (ciliopathies). It is accepted that the development of metabolic syndrome and obesity stems from the interaction of environmental factors with genetic factors. However, how dysfunctional cilia cause obesity remains poorly understood.

Obesity is a component of metabolic syndrome and a risk factor for type 2 diabetes mellitus. These conditions represent a major global pandemic and health crisis. Interestingly, some obese patients remain metabolically healthy despite their increased body weight. This phenomenon is known as "healthy obesity."

It is possible that obesity by itself may not be the main cause of metabolic dysfunction observed in metabolic syndrome, but rather, the failure of fat tissue to store fat. Thus, the proper storage of fat in adipocytes and the prevention of fat tissue inflammation and dysfunction may lead to a "metabolically healthy" phenotype, despite increase in food intake and body weight.

Potential outcomes and advances: The team has established that depletion of FBF1 in mice causes obesity and enhanced adipocyte differentiation. However, unlike the shortened life spans of other mice in which obesity is induced through genetics or diet, the life span of FBF1 mice is completely normal, suggesting that cilia dysfunction caused by FBF1 depletion may protect obese mice from adverse metabolic disorders.

It is possible that FBF1 may be involved in the development of metabolic syndrome by preventing adipogenesis, causing fat tissue dysfunction and "spillover" of fat to other tissues such as the liver, skeletal muscle and arteries. By further characterizing FBF1 mutant mice, the team aims to understand whether and how FBF1 mutant mice are protected from metabolic disorders.

The investigative team will then extend its research to explore the correlation between cilia and human adipocyte differentiation as well as common obesity. The team expects to obtain firsthand, seminal information from these studies, which will help to understand the causes, consequences, prevention and treatment of obesity and associated metabolic disorders.

Title: Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia

Clinical intermittent hypoxia studies

Investigative team: Michael D. Jensen, M.D., Prachi Singh, Ph.D.

Central hypothesis: People with sleep apnea temporarily stop breathing many times while they are asleep. This results in too little oxygen in the bloodstream, which causes a large number of stress responses that severely damage health. One of these responses is the release of a hormone called endothelin-1. Endothelin-1 may play a central role in how sleep apnea predisposes people to other diseases such as diabetes.

In this project, the investigative team is studying how a medication (bosentan) that prevents endothelin-1 from acting on tissues affects the stress response to low oxygen in the bloodstream. The team is conducting the initial studies in healthy adults who are exposed to low blood oxygen levels by having them breathe air that has less oxygen.

Potential outcomes and advances: By measuring how much of the stress response is prevented by the administration of the bosentan, the team expects to determine whether this medication could improve the health of people with sleep apnea.