To identify the proximate targets of high-fat diet consumption in the circadian system, we measured tissue rhythms in mice fed a high-fat diet for 1 week. We found that the phases of the rhythms in all of the central and peripheral tissues that we measured were resistant to 1 week of high-fat diet consumption, with the exception of the liver. The phase of the liver was markedly advanced by 5 h in mice eating a high-fat diet ad libitum
compared with mice consuming chow. As the phase of the tissue liver clock is altered by meal timing (Stokkan et al., 2001
), we hypothesized that the change in the timing of the liver clock during high-fat diet consumption resulted from a change in the eating behavior rhythm.
To measure the effect of high-fat diet consumption on the daily rhythm of eating behavior, we continuously monitored behavior with an infrared camera. Individual mice were first provided with ad-libitum
access to standard chow and then were switched to ad-libitum
high-fat diet. During chow consumption, the majority of mouse eating behavior was confined to the dark phase, with several consolidated eating bouts during the light phase. Eating behavior was immediately affected by consumption of a high fat diet, such that eating events became more evenly distributed across the day and night. In a previous study, Kohsaka et al. (2007)
measured the daily rhythm of food intake (instead of eating behavior as measured in this study) in mice fed a high-fat diet. They found that 1 week of a high-fat diet caused an approximate 20% increase in food intake in the light phase compared with mice eating chow. Even with this change, the high-fat diet consumption of mice was clearly rhythmic, with ~30% of food intake occurring during the light phase and ~70% of food intake occurring during the dark phase. In this study, we found that the rhythm of eating behavior was drastically affected by consumption of a high-fat diet. By measuring different outputs (eating behavior vs. food intake), we may be distinguishing distinct mechanisms controlling different aspects of eating.
Regardless of whether eating behavior or food intake is measured, it is clear that a high-fat diet rapidly and robustly affects daily eating patterns. Furthermore, numerous studies have linked disruptions in the daily rhythm of food intake with weight gain (Mistlberger et al., 1998
; Turek et al., 2005
; Arble et al., 2009
; Fonken et al., 2010
; Hatori et al., 2012
; Morales et al., 2012
). Thus, understanding the mechanisms that regulate daily rhythms of eating, and how they are altered by the macronutrient content of food, is critical to understanding body weight regulation.
As eating behavior is immediately affected by consumption of a high-fat diet, a first step in investigating these mechanisms is to identify the brain regions that are acutely altered by eating a high-fat diet. We found that the phase, amplitude, and period of the tissue SCN rhythm were not affected by 1 week of high-fat diet consumption; thus it is likely that target nuclei are components of the homeostatic brain circuits downstream of the SCN. In this study, we measured the rhythm of the arcuate complex, which participates directly in regulating food intake. We found that the phase of the rhythm in the arcuate complex was not altered by 1 week of a high-fat diet, but we could not use statistics to analyze the amplitude of the rhythm due to the low level of light emitted from this tissue. An in-vivo
technique, such as measuring multi-unit neural activity from freely moving mice (Nakamura et al., 2008
), may be ideal for identifying neural substrates that are altered by high-fat consumption. Measuring the acute effects of a high-fat diet on other physiological outputs, such as body temperature rhythms, will also provide insight into the neural loci that are affected by a high-fat diet.
This study also provides insight into how a high-fat diet affects distinct regulatory processes controlling food intake. Eating is regulated by homeostatic mechanisms, which balance food intake with energy expenditure, and by the circadian system, so that the majority of food intake occurs during the active phase. The SCN is critical for circadian control of eating as the eating rhythm is abolished in SCN-lesioned rats (Nagai et al., 1978
). Interestingly, circadian and homeostatic regulation of eating can be dissociated in certain conditions. For example, when rodents are provided with food for only several hours during the day (their inactive phase), they exhibit food anticipatory activity and readily consume food during the day (Mistlberger, 2009
). This restricted feeding protocol does not change the phase of the SCN rhythm (Stokkan et al., 2001
) (if the rodents are not calorically restricted), demonstrating that homeostatic and circadian control of eating are modulated by distinct neural circuitry. We observe a similar phenomenon with high-fat diet consumption; the timing of eating behavior is immediately and robustly affected by a high-fat diet, but the tissue rhythm in the SCN is unaffected. In contrast, the liver rhythm is acutely altered by a high-fat diet. Whether the liver rhythm shifts as a consequence of the change in eating behavior or due to a direct effect of high fat on the liver should be investigated in future studies. As a high-fat diet is highly palatable, the reward system also participates in the control of eating in this paradigm. By modulating the macronutrient content of food, we can distinguish the circadian, homeostatic, and reward circuits modulating eating behavior.