High-fat feeding alters the clock synchronization to light

Abstract

High-fat feeding in rodents leads to metabolic abnormalities mimicking the human metabolic syndrome, including obesity and insulin resistance. These metabolic diseases are associated with altered temporal organization of many physiological functions. The master circadian clock located in the suprachiasmatic nuclei controls most physiological functions and metabolic processes. Furthermore, under certain conditions of feeding (hypocaloric diet), metabolic cues are capable of altering the suprachiasmatic clock's responses to light. To determine whether high-fat feeding (hypercaloric diet) can also affect resetting properties of the suprachiasmatic clock, we investigated photic synchronization in mice fed a high-fat or chow (low-fat) diet for 3 months, using wheel-running activity and body temperature rhythms as daily phase markers (i.e. suprachiasmatic clock's hands). Compared with the control diet, mice fed with the high-fat diet exhibited increased body mass index, hyperleptinaemia, higher blood glucose, and increased insulinaemia. Concomitantly, high-fat feeding led to impaired adjustment to local time by photic resetting. At the behavioural and physiological levels, these alterations include slower rate of re-entrainment of behavioural and body temperature rhythms after 'jet-lag' test (6 h advanced light-dark cycle) and reduced phase-advancing responses to light. At a molecular level, light-induced phase shifts have been correlated, within suprachiasmatic cells, with a high induction of c-FOS, the protein product of immediate early gene c-fos, and phosphorylation of the extracellular signal-regulated kinases I/II (P-ERK). In mice fed a high-fat diet, photic induction of both c-FOS and P-ERK in the suprachiasmatic nuclei was markedly reduced. Taken together, the present data demonstrate that high-fat feeding modifies circadian synchronization to light.

Figure 1

Time schedule of feeding and lighting conditions over the 3 months of the experiment.

Figure 2

Pooled data of body mass gain (A), body mass index (B), mass of white adipose (epididymal) tissue (C) and homeostatic model assessment of insulin resistance (HOMA-ir; D) in mice fed with a low- or high-fat diet (n = 16 per feeding condition). Blood glucose (E), plasma insulin (F), leptin (G) and corticosterone (CORT; H) in mice fed with low- or high-fat diet sampled at projected circadian times (CT) 13 or 22 (n = 7–8 per CT and feeding condition), data for ‘dark’ and ‘light’ groups being pooled. *P < 0.05 between feeding conditions for a given CT.

Figure 3

Daily profiles of wheel-running activity (A and B) and body temperature (C and D) in mice during baseline (low-fat diet; A and C) and during high-fat (◊; n = 16) or low-fat feeding (•; n = 16). *P < 0.05 between feeding conditions for the time points below the horizontal lines.

Figure 4

Daily double-plotted rhythms (A–D) and rate of re-entrainment (E–H) of wheel-running activity (A and B, and E and F) and body temperature (C and D, and G and H) in mice fed a low-fat (A and C, and black bars in panels E–H; n = 16) or high-fat diet (B and D, and grey bars in panels E–H; n = 16) and successively challenged by 6 h advance (1st arrow) and 6 h delay of the light–dark cycle (2nd arrow). *P < 0.05 between feeding conditions.

Figure 5

Light-induced phase shifts in circadian rhythms of wheel-running activity (A–D and I) and body temperature (E–H and J) in low-fat- (A, C, E and G, and black bars in I and J; n = 16) or high-fat-fed mice (B, D, F and H, and grey bars in I and J; n = 16) housed in constant darkness. Circadian time (CT) 12 being defined as the activity onset, mice were exposed to a light pulse at CT13 (A and B, E and F, and I and J) or CT22 (C and D, G and H, and I and J). *P < 0.05 between feeding conditions for a given time point.

Figure 6

c-FOS and P-ERK responses to light exposure at night in the suprachiasmatic nuclei of mice fed a low- or high-fat diet. Mice were exposed (‘Light’; n = 4) or not exposed (‘Dark’; n = 4) to a light pulse at CT13 or CT22. *P < 0.05 between feeding conditions, #P < 0.05 between dark and light conditions. Scale bar = 500 μm. ROD: relative optical density.