Skeletal muscle capillaries are critical determinants of nutrient delivery and utilization and capillary network density is thought to correlate with insulin sensitivity. Conflicting data exist regarding the consequence of obesity‐associated metabolic disturbances on skeletal muscle capillarization, with positive, negative and no effect having been reported. The purpose of this investigation is to assess the influence of obesity induced by high fat feeding or by leptin receptor mutation, on the angiogenic profile within the skeletal muscle microenvironment, and ultimately, on muscle capillarization. In FVB/n mice fed a high‐fat (HF) or normal chow (NC) diet for 16‐weeks, mRNA levels of VEGF‐A did not change (NC: 1.06 vs. HF: 1.13; P>0.05) but VEGF protein levels were elevated (NC: 81 vs HF: 104 pg/mg; P =0.02). Relative FoxO1 protein levels increased in capillaries isolated from muscle of HF vs. NC mice (NC: 0.67 vs HF: 1.55; P =0.03). Capillary‐to‐fibre ratio (C:F) was not altered in HF‐ compared to NC‐ fed mice (2.22 and 2.04, P=0.34). In contrast, 13 week old mice with leptin receptor activity deficiency (Leprdb) had a significant reduction in VEGF‐A mRNA (1.85 vs. 1.09, P=0.03) and protein (WT: 98 vs Leprdb: 86 pg/mg; P<0.05) relative to age‐matched C57BL/6 (WT) mice. Both FoxO1 (0.58 vs. 0.86) and THBS1 (0.37 vs. 0.81) mRNA levels tended to increase in Leprdb vs. WT mice. Skeletal muscle C:F was substantially reduced in Leprdb vs. WT mice (1.92 vs. 1.39, P<0.001). Comprehensive profiling of angiogenic regulators will be conducted by microarray analysis. The skeletal muscle microenvironment differs substantially between HF and Leprdb models. Our data suggest that muscle capillarization is maintained during HF feeding due to a balance between pro and anti‐angiogenic factors, which may include VEGF‐A and FoxO1. This balance is disrupted in leptin receptor mutant mice, which results in a loss of capillaries and raises the intriguing possibility that leptin signaling itself modulates muscle capillarization. Thus, the Leprdb model may not be a suitable model to study obesity‐induced vascular alterations in skeletal muscle. Funded by CIHR.