AbstractThe effect of diet composition on diurnal changes in glycogen zonation patterns in rat liver was investigated in individually‐caged male Sprague‐Dawley rats adapted to the 2 + 22 controlled feeding and lighting schedule and to diets containing 30% casein/55% carbohydrates, 60% casein/25% carbohydrates, or 90% casein (30 rats/dietary group). Three rats from each dietary group were killed at the following times relative to the onset of feeding (0 min):−60, −30, 0, 15, 30, 45, 60, 90, 120, and 180 min. Glycogen in cryostat sections from the median and right lateral lobes of the liver was fixed and stained by standard techniques. The optical density of glycogen at points along the path between the central and portal veins of a given lobule was determined, and lobular glycogen gradients of replicate animals were integrated to form a composite lobular glycogen distribution profile. In the period from −60 to 0 min, liver glycogen levels were similar for rats on any of the diets, and the glycogen concentration was similar in periportal (P), midlobular (M), and centrilobular (C) hepatocytes. During the 0‐ to 45‐min period, diet‐related glycogen depletion occurred (90>60 ≫ 30% casein) by asymmetrical glycogen loss (P>M ≫ C hepatocytes) from the liver lobules. Similar food intake curves occurred for all diets. During the 45‐ to 180‐min period, asymmetrical glycogen accumulation began in lobular parenchymal cells (P>M ≫ C hepatocytes), and the rate of accumulation was related to dietary composition (30>60 ≫ 90% casein). The differential responses of parenchymal cells within liver lobules to physiological stimuli resulted in glycogen distributional changes that were rapid and of large magnitude. Our results are consistent with the hypothesis that periportal and midlobular hepatocytes are more metabolically responsive and active tha