Why do our waistlines expand in middle age?

It’s no secret that our waistlines often widen in middle age, which can cause problems for our health: belly fat accelerates aging and slows down metabolism, increasing our risk for developing diabetes, heart problems and other chronic diseases. Now preclinical research led by City of Hope has uncovered the cellular culprit behind age-related abdominal fat, with results published in the journal Science.

As noted by Dr Qiong (Annabel) Wang, the study’s co-corresponding author and an associate professor at City of Hope’s Arthur Riggs Diabetes & Metabolism Research Institute, “People often lose muscle and gain body fat as they age — even when their body weight remains the same.” Seeking to investigate this, the research team conducted a series of mouse experiments later validated on human cells. Wang and her colleagues focused on white adipose tissue (WAT), the fatty tissue responsible for age-related weight gain.

While it’s well-known that fat cells grow larger with age, the scientists suspected that WAT also expanded by producing new fat cells, meaning it may have an unlimited potential to grow. The researchers focused on adipocyte progenitor cells (APCs), a group of stem cells in WAT that evolve into fat cells.

The team first transplanted APCs from young and older mice into a second group of young mice. The APCs from the older animals rapidly generated a colossal amount of fat cells. When the team transplanted APCs from young mice into the older mice, however, the stem cells did not manufacture many new fat cells. This confirmed that older APCs are equipped to independently make new fat cells, regardless of their host’s age.

Using single-cell RNA sequencing, the scientists next compared APC gene activity in young and older mice. While barely active in young mice, APCs began pumping out new fat cells in middle-aged mice.

“While most adult stem cells’ capacity to grow wanes with age, the opposite holds true with APCs — aging unlocks these cells’ power to evolve and spread,” said Dr Adolfo Garcia-Ocana, Chair of the Department of Molecular & Cellular Endocrinology at City of Hope. “This is the first evidence that our bellies expand with age due to the APCs’ high output of new fat cells.”

Aging also transformed the APCs into a new type of stem cell called committed preadipocytes, age-specific (CP-As). Arising in middle age, CP-A cells actively churn out new fat cells, explaining why older mice gain more weight. A signalling pathway called leukaemia inhibitory factor receptor (LIFR) proved critical for promoting these CP-A cells to multiply and evolve into fat cells.

“We discovered that the body’s fat-making process is driven by LIFR,” Wang said. “While young mice don’t require this signal to make fat, older mice do. Our research indicates that LIFR plays a crucial role in triggering CP-As to create new fat cells and expand belly fat in older mice.”

Using single-cell RNA sequencing on samples from people of various ages, Wang and her colleagues next studied APCs from human tissue in the lab. Again, the team also identified similar CP-A cells that had an increased number in middle-aged people’s tissue. Their discovery also illustrates that CP-As in humans have high capacity in creating new fat cells.

“Our findings highlight the importance of controlling new fat-cell formation to address age-related obesity,” Wang said. “Understanding the role of CP-As in metabolic disorders and how these cells emerge during aging could lead to new medical solutions for reducing belly fat and improving health and longevity.”

Image credit: iStock.com/Suriyawut Suriya