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The intracellular steps of chylomicron biogenesis and transport from the Endoplasmic Reticulum (ER) to the Golgi complex have been described, but the mechanisms for post-Golgi transport and secretion of chylomicrons have not been identified. Using a newly generated <jats:italic>Dennd5b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse, we demonstrate an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. In mice, loss of <jats:italic>Dennd5b<\/jats:italic> results in resistance to western diet induced obesity, changes in plasma lipids, and reduced aortic atherosclerosis. In humans, two independent exome sequencing studies reveal that a common <jats:italic>DENND5B<\/jats:italic> variant, p.(R52K), is correlated with body mass index. 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