LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Background WNT signaling plays a key role in postnatal bone formation. Individuals with gain-of-function mutations in the WNT co-receptor LRP5 exhibit increased lower-body fat mass and potentially enhanced glucose metabolism, alongside high bone mass. However, the mechanisms by which LRP5 regulates fat distribution and its effects on systemic metabolism remain unclear. This study aims to explore the role of LRP5 in adipose tissue biology and its impact on metabolism. Methods Metabolic assessments and imaging were conducted on individuals with gain- and loss-of-function LRP5 mutations, along with age- and BMI-matched controls. Mendelian randomization analyses were used to investigate the relationship between bone, fat distribution, and systemic metabolism. Functional studies and RNA sequencing were performed on abdominal and gluteal adipose cells with LRP5 knockdown. Results Here we show that LRP5 promotes lower-body fat distribution and enhances systemic and adipocyte insulin sensitivity through cell-autonomous mechanisms, independent of its bone-related functions. LRP5 supports adipose progenitor cell function by activating WNT/β-catenin signaling and preserving valosin-containing protein (VCP)-mediated proteostasis. LRP5 expression in adipose progenitors declines with age, but gain-of-function LRP5 variants protect against age-related fat loss in the lower body. Conclusions O

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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