Why do fat cells keep filling?

What tells a fat cell to keep filling?

Fat tissue grows mostly by hypertrophy: existing adipocytes swell with triglyceride. The steps that let a cell keep adding lipid are still largely unknown, partly because hypertrophied adipocytes cannot be isolated from a living person to study.

When we lowered the zinc finger protein Zfp949 in adipocytes, the cells stored significantly more triglyceride than controls throughout differentiation. Zfp949 had only been described as a transcriptional suppressor during embryonic development. We think it holds back the genes and proteins that drive lipid buildup, and that raising it could protect cells from hypertrophy.

With RNA sequencing, proteomics and lipidomics, we are mapping what changes when Zfp949 falls, and testing whether overexpressing it is a route to preventing or treating obesity.

Is a receptor built to help us store fat now driving obesity?

Advanced glycation end products (AGEs) form when sugars react with proteins and fats. Highly processed foods are rich in them, and the body makes more when blood sugar runs high. AGEs signal through RAGE, a receptor on adipocytes, and its intracellular partner DIAPH1.

At NYU, Dr. Ruiz and colleagues found that high AGE levels disrupt glucose metabolism and that RAGE tracks with lipid accumulation and obesity in mice and in human tissue. In people with obesity, the AGE/RAGE/DIAPH1 axis was tied to insulin-resistance risk in subcutaneous fat but not in omental fat. The work points to RAGE as a lipid-storage mechanism that helped in lean times and works against us when food is always available.

Mice lacking DIAPH1 in their fat resisted diet-induced obesity and carried more Zfp949. That result started the Zfp949 project.

Do AGEs in the brain cause insulin resistance and feed Alzheimer’s disease?

The hypothalamus helps set how the body handles glucose and fat.

At the Icahn School of Medicine at Mount Sinai, Dr. Ruiz showed that mice engineered to model Alzheimer’s disease were more prone to metabolic dysregulation, with impaired insulin signaling in the hypothalamus and elevated branched-chain amino acids. The results suggest that Alzheimer’s disease and diabetes can drive each other.

Later, at NYU, he found that AGEs build up in brains affected by Alzheimer’s disease. The lab now asks whether those AGEs cause insulin resistance and impaired glucose metabolism, and whether that helps trigger or worsen the disease.