The objective of this study was to determine the effect of AVE7688, a drug that inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) activity, on neural and vascular defects caused by diet induced obesity (DIO). Rats at 12 weeks of age were fed a standard or high fat diet with or without AVE7688 for 24 weeks. DIO rats had impaired glucose tolerance and developed sensory neuropathy. Vascular relaxation to acetylcholine and calcitonin gene-related peptide was decreased in epineurial arterioles of DIO rats. Rats fed a high fat diet containing AVE7688 did not become obese and vascular and sensory nerve dysfunction and impaired glucose tolerance were improved. DIO is associated with increased expression of NEP in epineurial arterioles. NEP degrades vasoactive peptides which may explain the decrease in neurovascular function in DIO.