The objective of this study was to determine the effect of diet induced obesity (DIO) on microvascular and neural function. Rats were fed a standard or high fat diet for 32 weeks. Vasodilation in epineurial arterioles was measured by videomicroscopy, endoneurial blood flow by hydrogen clearance, nerve conduction velocity following electrical stimulation of motor or sensory nerves and thermal nociception using the Hargreaves method. Rats fed a high fat diet developed sensory neuropathy as indicated by slowing of sensory nerve conduction velocity and thermal hypoalgesia. Motor nerve conduction velocity and endoneurial blood flow was not impaired. Vascular relaxation to insulin was potentiated in epineurial arterioles from high fat fed rats. In contrast, relaxation to acetylcholine (ACH) and calcitonin gene-related peptide (CGRP) was attenuated. Expression of neutral endopeptidase (NEP) increased in epineurial arterioles of rats fed a high fat diet. We found that a high fat diet causes microvascular and neural dysfunction in a DIO rat model. This is associated with increased expression of NEP in epineurial arterioles. NEP degrades vasoactive peptides which may explain the decrease in microvascular function in response to ACH and CGRP. We conclude that the high fat fed Sprague Dawley rat is valuable as a model of vascular dysfunction associated with obesity as vascular changes are observed without dramatic metabolic changes. Although epineurial responses to ACH and CGRP are attenuated, relaxation to insulin is potentiated, suggesting adaptation to the insulin resistant state.