Summary: Stimulating the formation of beige fat — a thermogenic subtype of white adipose tissue — can reverse age-related declines in metabolic activity. These findings point to new approaches to prevent age-associated weight gain and metabolic disorders.
Source: Cornell University
New research identifies a biological pathway that limits the formation of energy-burning beige fat with age and demonstrates that blocking this pathway can restore beige fat production, offering a potential strategy to counteract aging-related metabolic decline.
Researchers in Cornell’s Division of Nutritional Sciences, housed in the College of Human Ecology and the College of Agriculture and Life Sciences, report that stimulating the production of beige adipocytes within white adipose tissue (WAT) can reverse metabolic slowing associated with aging. This approach could help prevent obesity and related conditions such as Type 2 diabetes, cardiovascular disease and chronic inflammation.
Mammals, including humans, possess at least two well-known types of fat: white adipose tissue, which stores excess energy, and brown adipose tissue (BAT), which burns calories to produce heat. A third, distinct form — beige fat — arises within WAT and combines features of both: it originates from white fat precursors but displays thermogenic, calorie-burning functions similar to brown fat. Beige adipocytes can therefore help lower blood glucose and reduce circulating fatty acids that contribute to arterial plaque and heart disease.
Cold exposure stimulates perivascular adipocyte progenitor cells to differentiate into thermogenic beige adipocytes within white fat. However, this capacity declines with age: older individuals lose the robust beige response seen in youth. “There are seasonal changes in beige fat in young humans,” said Dan Berry, assistant professor in the Division of Nutritional Sciences, “but an older person would have to stand outside in the snow in their underwear to get those same effects.”
In prior work, Berry and colleagues observed that aged adipose progenitor cells fail to generate beige fat effectively in response to cold. The new study identifies a key biochemical mechanism underlying that failure and shows how reversing it can reinstate beige adipogenesis in older animals.
Lead author Abigail Benvie, a doctoral student in Berry’s lab, explained the therapeutic aim: “Without having to subject people to prolonged cold exposure, can we activate metabolic pathways that produce the same beneficial effects?” The current study demonstrates that targeting a specific signaling pathway achieves that goal in male mice.
The investigators found that platelet-derived growth factor receptor beta (Pdgfrβ) signaling becomes overactive in aging adipocyte progenitor cells and suppresses beige adipocyte formation. This signaling axis interferes with local immune signals that normally promote beige fat development. By genetically deleting or pharmacologically inhibiting Pdgfrβ signaling in older mice, the team was able to restore the generation of beige adipocytes within white fat depots. Conversely, activating Pdgfrβ in juvenile mice blocked beige formation.
Mechanistically, the study shows that Pdgfrβ signaling in aged progenitor cells increases Stat1 phosphorylation, which suppresses the induction of the immune cytokine IL-33 and downstream immunological factors such as IL-13 and IL-5. Restoring immune niche function by targeting Pdgfrβ rescues beige adipogenesis, indicating that immune–progenitor cell interactions are central to age-related loss of thermogenic capacity in WAT.
These observations were made in controlled experiments with male mice and point to a reproducible pathway that can be modulated to rejuvenate adipose tissue function. The research team included graduate students Derek Lee, Benjamin M. Steiner and Siwen Xue, and collaborator Yuwei Jiang from the University of Illinois at Chicago. Funding for the project came from a five-year, $2.2 million grant from the National Institutes of Health, which will support further investigation into Pdgfrβ signaling and other molecular regulators of beige adipocyte development during aging.
Restoring beige fat in aging mammals could reduce excess fat mass, improve glucose regulation and lower circulating lipids that promote cardiovascular disease. While these results are preclinical, they establish a promising direction for therapies aimed at reactivating beneficial thermogenic programs in white fat without relying on cold exposure.
About this metabolism research news
Author: Becka Bowyer
Source: Cornell University
Contact: Becka Bowyer – Cornell University
Image: The image is in the public domain
Original Research: Open access. “Age-dependent Pdgfrβ signaling drives adipocyte progenitor dysfunction to alter the beige adipogenic niche in male mice” by Dan Berry et al. Nature Communications
Abstract
Age-dependent Pdgfrβ signaling drives adipocyte progenitor dysfunction to alter the beige adipogenic niche in male mice
Perivascular adipocyte progenitor cells (APCs) can generate cold-induced thermogenic beige adipocytes within white adipose tissue (WAT), an effect that could counteract excess fat mass and metabolic pathologies. However, the ability to generate beige adipocytes declines with age, limiting therapeutic potential.
This study shows that ageing beige APCs overexpress platelet-derived growth factor receptor beta (Pdgfrβ), which prevents beige adipogenesis. Genetically deleting Pdgfrβ in adult male mice restores beige adipocyte generation, whereas activating Pdgfrβ in juvenile mice blocks beige fat formation.
Mechanistically, Stat1 phosphorylation mediates Pdgfrβ signaling in beige APCs to suppress IL-33 induction, which in turn dampens immunological genes such as IL-13 and IL-5. Pharmacologically targeting Pdgfrβ signaling restores beige adipocyte development by rejuvenating the local immunological niche.
These findings suggest that targeting Pdgfrβ signaling could be a strategy to restore white adipose tissue immune cell function and stimulate beige fat formation in adult mammals, potentially improving metabolic health during aging.