Obesity does not depend solely on the amount of body fat accumulated but also on how and where that fat is distributed throughout the body. Visceral adipose tissue—the fat that accumulates around internal organs—is associated with a higher risk of diabetes, chronic inflammation, and cardiovascular disease. Understanding the mechanisms that regulate its expansion is one of the major current challenges in biomedical research.
A study led by Dr. Maria Borrell from the Sant Pau Research Institute (IR Sant Pau) has now identified the key role of the LRP5 protein in adipose tissue growth and in the inflammatory processes associated with obesity. The work, published in the journal Journal of Cellular and Molecular Medicine, demonstrates in experimental models that the absence of this protein significantly reduces both fat accumulation and the infiltration of inflammatory cells induced by high-fat, high-cholesterol diets.
The research was carried out by investigators from the Molecular Pathology and Therapeutics of Ischemic and Atherothrombotic Diseases group at IR Sant Pau and CIBERCV, with participation from researchers affiliated with the Biomedicine doctoral program at the Universitat de Barcelona.
“Our results indicate that LRP5 is involved not only in adipose tissue expansion but also in the inflammatory response that accompanies visceral fat growth,” explains Dr. Maria Borrell. “This reinforces the idea that obesity and inflammation are deeply interconnected processes and that certain molecular pathways could become future therapeutic targets.”
The study analyzed normal mice and genetically modified mice lacking functional LRP5 expression, which were fed a high-fat, high-cholesterol diet for eight weeks to assess how different adipose tissue depots responded to a state of lipid overload.
The researchers observed marked differences between the two groups. While normal mice gained approximately 9 grams of body weight, LRP5-deficient animals increased their weight by only around 2.5 grams, representing nearly a 70% reduction in weight gain following the high-fat diet. In addition, mice lacking LRP5 accumulated significantly less visceral and subcutaneous fat, two adipose depots most closely associated with cardiometabolic risk.
This effect was particularly striking because the LRP5-deficient animals simultaneously exhibited higher circulating LDL cholesterol levels. According to the authors, this suggests that the absence of LRP5 limits the ability of adipose tissue to expand and store lipids even under metabolically unfavorable conditions.
The work also demonstrates that the expression of LRP5 and another related lipid receptor, LRP1, increases in visceral and subcutaneous adipose tissue following high-fat diets, and a similar pattern was observed in human adipose tissue samples from individuals with obesity.
“The data suggest that these proteins actively participate in the ability of adipose tissue to expand and store lipids. This is especially relevant because uncontrolled expansion of visceral adipose tissue is directly associated with metabolic and cardiovascular complications,” says Dr. Maria Borrell.
Another important finding is the relationship between LRP5 and the infiltration of inflammatory cells into adipose tissue. Normal mice fed a high-fat diet showed increased macrophage accumulation and inflammatory markers in adipose tissue. In contrast, animals lacking LRP5 exhibited a significant reduction in this inflammatory response.
“Visceral fat is not merely an energy storage depot. It is a highly metabolically active tissue capable of generating inflammatory signals that can affect multiple organs,” adds Dr. Maria Borrell. “Understanding how this interaction between metabolism and inflammation is regulated is essential for developing new strategies against cardiometabolic diseases.”
LRP5 is part of the canonical WNT signaling pathway involved in cellular proliferation, tissue differentiation, and metabolic regulation. Although this pathway had previously been associated with bone metabolism and with some mechanisms involved in body fat distribution, its role in adipose tissue expansion and obesity-associated inflammation remained poorly understood. The study findings help explain why visceral fat is associated with increased cardiometabolic risk.
Although this is still preclinical research, the work opens new avenues for studying how modulation of this molecular pathway could, in the future, help limit pathological adipose tissue expansion or reduce obesity-associated inflammation.
The study received funding from several national and regional biomedical and cardiovascular research support programs, including projects funded by the Instituto de Salud Carlos III, La Marató de TV3, the Ministry of Science and Innovation, and the Generalitat de Catalunya.
Luquero A, Pimentel N, Vilahur G, Badimon L, Borrell-Pages M. Reduced growth and inflammation in Lrp5-/- mice adipose tissue. J Cell Mol Med 2025;29:e70670. https://doi.org/10.1111/jcmm.70670 ArAardjfsjPrincipio del formulario
