Baseline study characteristics.

<p>Data are presented as mean ± SEM, ND not determined, LFD low fat diet, HFD high fat diet, WT wildtype, PC Phosphatidylcholine, BW body weight.</p

Genetic deficiency of CD40L does not protect from diet-induced obesity.

<p>WT and CD40L^−/− mice consumed a high fat diet (HFD) for 20 weeks. Relative increase of body weight (shown as % of body weight at week 0) and total body fat as assessed by MRI-based body composition analysis are shown for the indicated time points (A, B). Weight of epididymidal (EFP), peri-renal (RFP), and cardiac fat pads (CFP) fat are displayed as percentage of total body weight (BW, C). Data are presented as mean ± SEM of at least 15 mice per group.</p

CD40L deficiency does not affect basic energy metabolism.

<p>WT and CD40L^−/− mice consumed a high fat diet (HFD) for 20 weeks. Plasma levels of leptin (A) and adiponectin (B) were determined at the indicated time points by ELISA. Food intake (C), heat production (D), ambulatory movement (E), and respiratory exchange ratio (RER, F) were analyzed in metabolic cages. CaH and fat indicate carbohydrate and fat metabolism (F). Data are presented as mean ± SEM of at least 9 mice per group.</p

Absence of CD40L does not ameliorate insulin sensitivity in diet-induced obesity.

<p>Plasma glucose (A) and insulin levels (B) were determined in animals fasted overnight (A) and for 6 hours (B) overnight. Insulin tolerance (ITT) and glucose tolerance testing (GTT) were performed after intraperitoneal insulin (0.5 U/kg lean body mass) or glucose (1 g/kg lean body mass) injection (C–F). Inlays represent area under the curve calculation (AUC) of the indicated glucose curve.</p

Genetic absence of CD40L reduces MCP-1 gene expression in adipose tissue and MCP-1 plasma levels.

<p>Diet-induced obesity was induced by feeding with a high fat diet for 20 weeks. MCP-1 gene transcripts in adipose tissue were quantified by quantitative PCR after whole tissue RNA preparation and normalization for GAPDH expression (A). Levels of circulating MCP-1 were determined in plasma by cytometric bead array. Data are presented as mean ± SEM of at least 6 animals per group.</p

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF