Summary: A cholesterol-derived molecule called 27-hydroxycholesterol (27HC) acts directly on white adipose tissue and promotes increased body fat, even when diet alone would not predict weight gain.
Source: University of Houston
One molecule derived from cholesterol — 27-hydroxycholesterol (27HC) — has been shown to increase body fat by acting directly on white adipose tissue. This effect can occur even in the absence of an overtly high-fat, high-cholesterol diet, although such diets raise 27HC levels and amplify weight gain.
Researchers at the University of Houston report in the journal Endocrinology that 27HC influences fat accumulation by altering adipose tissue behavior. “We found 27HC directly affects white adipose (fat) tissue and increases body fat, even without eating the diet that increases body fat,” says Michihisa Umetani, assistant professor of biology at the University of Houston. Lead author and doctoral student Arvand Asghari adds, “But it does need some help from the diet to increase body weight because it expands the capacity of the fat already in the body.”
The team suggests that long-term applications of this work could lead to therapeutic strategies aimed at lowering circulating 27HC. Reducing 27HC levels may limit the body’s capacity to form and expand fat tissue and could have relevance for diseases linked to cholesterol and estrogen signaling, including cardiovascular disease, osteoporosis, certain cancers, and metabolic disorders. Umetani’s lab is part of the UH Center for Nuclear Receptors and Cell Signaling.
Prior studies had identified 27HC as an abundant cholesterol metabolite with harmful cardiovascular effects. What this new study adds is a clearer picture of how 27HC promotes adiposity by acting directly on white adipose tissue and by stimulating inflammatory responses within fat depots.
Role of estrogen receptors
Estrogen signaling influences fat distribution and accumulation in both sexes. In women, the decline in estrogen at menopause is associated with increased adiposity and faster weight gain, indicating that estrogen normally protects against excessive fat accumulation. In men, local conversion of testosterone to estrogen contributes to estrogen signaling and may impact fat tissue development as well.
Estrogen receptors, particularly ERα, are members of the nuclear receptor family and are present in adipocytes (fat cells). According to Umetani, patients lacking functional ERα develop obesity and accumulate more fat tissue even when their food intake matches that of individuals with a functioning receptor. This highlights ERα as a key isoform for estrogen-mediated regulation of adipose tissue.
In the liver, one normal function of 27HC is to help remove excess cholesterol. Umetani’s earlier work showed that 27HC can bind estrogen receptors and act as an inhibitor of ER signaling in blood vessels. The current study reinforces that 27HC’s effects vary by tissue, identifying 27HC as the first naturally produced selective estrogen receptor modulator (SERM) that influences adipose tissue behavior.
Source:
University of Houston
Media Contacts:
Laurie Fickman – University of Houston
Image Source:
Image credited to the University of Houston.
Original Research:
“27-Hydroxycholesterol Promotes Adiposity and Mimics Adipogenic Diet-induced Inflammatory Signaling.” Arvand Asghari, Tomonori Ishikawa, Shiro Hiramitsu, Wan-Ru Lee, Junko Umetani, Linh Bui, Kenneth S. Korach, Michihisa Umetani. Endocrinology. DOI: 10.1210/en.2019-00349 (closed access).
Abstract (summary)
27-Hydroxycholesterol (27HC) is an abundant cholesterol metabolite previously linked to negative cardiovascular outcomes; its role in adiposity was less understood. This study shows that increased 27HC raises body weight gain in mice consuming a high-fat, high-cholesterol diet in an estrogen receptor α-dependent manner. Independent of diet, 27HC increased body fat mass without altering food intake or fat absorption. In mice fed normal chow, 27HC did not change overall energy expenditure but did expand visceral white adipose tissue by promoting hyperplasia (increasing adipocyte precursor populations) rather than hypertrophy (enlarging existing fat cells). Although 27HC did not drive terminal adipocyte differentiation directly, it increased the number of precursor cells that proceed to mature adipocytes. RNA sequencing revealed that 27HC treatment in mice on normal chow induced inflammatory gene expression patterns similar to those triggered by a high-fat/high-cholesterol diet. Histology showed an increase in total macrophages and pro-inflammatory M1-type macrophages in white adipose tissues after 27HC exposure. Together, these findings indicate that 27HC promotes adiposity by directly modulating white adipose tissue and enhancing adipose inflammation. Lowering serum 27HC may offer a cholesterol-targeted approach to prevent diet-induced obesity.