Fat Tissue Protein PCPE-1 Drives Heart Stiffness in Aging and Obesity

Heart failure with preserved ejection fraction (HFpEF) — characterized by a stiff, poorly relaxing left ventricle despite normal pumping strength — is a growing epidemic with extremely limited treatment options. Myocardial fibrosis is central to its pathology, yet no fibrosis-targeting therapies have been validated. This study set out to identify novel druggable mediators of cardiac fibrosis arising from brown adipose tissue (BAT), an organ increasingly recognized as a metabolic and endocrine hub.

Using bulk RNA sequencing of BAT from young (3-month) versus aged (19-month) mice on normal diets, the researchers identified procollagen C-endopeptidase enhancer-1 (PCPE-1) — encoded by the gene Pcolce — as one of the top upregulated secreted proteins with aging. PCPE-1 enhances enzymatic cleavage of procollagen C-propeptides, a rate-limiting step in fibrillar collagen assembly. Single-cell RNA-seq databases confirmed PCPE-1 is preferentially expressed in BAT mesenchymal stem cells, and differentiated brown adipocytes showed higher Pcolce levels than cardiac fibroblasts.

Mechanistically, aged BAT exhibited mitochondrial dysfunction (ballooning, cristae loss), elevated reactive oxygen species (ROS), oxidative DNA damage (8-OHdG, γH2AX), and activation of the c-Fos/c-Jun (AP-1) transcription factor complex. In vitro, exposing differentiated brown adipocytes to doxorubicin or hydrogen peroxide replicated this cascade and increased Pcolce expression — an effect blocked by AP-1 inhibition. This contrasts with the ER stress/IRE1/JNK pathway previously shown to drive PCPE-1 in obesity, indicating distinct upstream triggers converge on the same AP-1 node.

In human cohorts, circulating PCPE-1 rose with age and was significantly elevated in hospitalized HFpEF patients versus non-HFpEF individuals with preserved ejection fraction. Multiple regression confirmed age — not BMI or common comorbidities — as the independent predictor of plasma PCPE-1. In obese HFpEF mouse models, both systemic PCPE-1 knockout (KO) and BAT-specific PCPE-1 KO ameliorated left ventricular fibrosis and diastolic dysfunction without affecting body weight or systolic function. Critically, systemic PCPE-1 KO also improved age-associated diastolic dysfunction in mice on normal diets. Conversely, BAT-specific PCPE-1 overexpression aggravated cardiac fibrosis and diastolic dysfunction, establishing causality.

These findings identify PCPE-1 as a BAT-derived profibrotic circulating factor that links two major HFpEF risk factors — aging and obesity — to cardiac stiffness through distinct but convergent signaling. Given the limited treatment landscape for HFpEF, PCPE-1 represents a compelling therapeutic target, with BAT serving as an accessible upstream source amenable to tissue-specific intervention.