Treat time matters: Untimely sugar consumption implicated in long-term energy imbalance

When to eat your sweet treat? A new study published in this issue by Muguerza et al. suggests that appropriately timed consumption of our favorite confectionaries may be important for long-term energy balance and preservation of our internal 24-h rhythms. The circadian (i.e., 24-h) clock plays a critical role across tissues of the body, where it intricately controls the temporal patterns of gene expression required to maintain important diurnal function within individual cells, and ultimately within individual organs. Though light is a primary entrainment cue for the master pacemaker of the brain, the suprachiasmatic nucleus (SCN) of the hypothalamus, food is an important Zeitgeber (or “time-giver”) for many peripheral organs,¹ where the circadian phase can adapt to the timing of energy intake, as opposed to adhering to the circadian organization provided by the SCN's entrainment to the light/dark cycle. Interestingly, a “misalignment” of the circadian clock across peripheral organs and the SCN is thought to be induced by mistimed energy intake patterns,¹ and is deleterious for metabolic health in humans and other organisms.² Both the timing of food intake and the quality of nutrient intake are important for maintaining temporal organization within the body and for driving normal patterns of circadian gene expression.³

In this issue, Muguerza et al. use nocturnal rats to test several metabolic and circadian effects of elevated sugar consumption (“sweet treats”) administered at activity onset (8 p.m., or Zeitgeber time ZT12) versus the onset of the rest phase (8 a.m, ZT0). Though the sweet treat dose was provided by syringe in the form of diluted sweetened condensed milk, equating to only a half teaspoon of sugar for human consumption, time of day of administration had a profound effect on several metabolic and circadian properties. First, consistent with a body of literature showing time-of-day effects of energy intake on body weight (reviewed in⁴), rats administered the excess sugar at rest onset ultimately gained more weight compared to rats who consumed the sweet treat at the activity onset, despite no changes in overall energy intake (Figure 1).

Importantly, while energy intake was not different between groups, rhythmicity of glucose was maintained only in the rats consuming the excess sugar at the activity onset. Interestingly, insulin rhythmicity was preserved in both groups, though rhythmic patterns were antiphase in the two feeding groups. Insulin signaling results in direct modification of proteins involved in the central transcriptional translational feedback loop of the circadian clock,⁵ suggesting possible uncoupling or misalignment of the circadian clock in vivo depending on the time at which the sweet treat was administered. Notably, the diurnal timing of sugar administration altered the circadian rhythms of several core clock genes in the hypothalamus, and a considerably lower number of serum metabolites (several of which are involved in energy metabolism) were rhythmic in the rats consuming the sweet treat at the onset of rest phase compared to the onset of the active phase.

One asset of the study design included the experimenters controlling for movement and possible changes in stress hormones when rats were perturbed by humans. For example, all rats were housed in the same room and required to approach the end of the cage at the save Zeitgeber time, regardless of whether or not they consumed the treat. Several important considerations should be reflected on, however. For example, what was a sweet treat for the rats would likely have a marginal impact on insulin secretion for most humans, where the sugar content of most foods is already considerably high. For example, in the United States, one of the countries with the highest sugar consumption in the world, an average individual consumes approximately 34 teaspoons of sugar a day according to the United States Department of Agriculture (https://www.ars.usda.gov/). This is probably not surprising, considering that an average sugary drink has in the range of 7–12 teaspoons of sugar per serving. In this study, rats were provided the sweet treat on a backdrop of vivarium chow diet, which consisted of 3.2% sugar, roughly one fifth of the percent consumed by an average adult in the United States. Still, considering the high sugar content of many snacks consumed worldwide, the study results can be extrapolated to the eating habits and patterns of humans, and the deleterious effects that timing can have on metabolism and energy balance.

Circadian disruption is associated with metabolic disease, including obesity and diabetes.⁶ In this context, time-restricted eating can be considered a form of circadian medicine, wherein timed application of intervention (in this case energy intake) can be used to target and exploit the circadian clock.⁷ The quote by Hippocrates, “Let food by thy medicine and medicine by thy food,” is often cited to emphasize the powerful impact of nutrition on health. Increasingly understood is the extent to which the timing of energy intake may be important for delaying metabolic disease and its progression. This study underscores that even the timing of snacks with sufficient calories to alter insulin secretion and blood glucose may be important for maintaining energy balance in the long term.

Kristin Eckel-Mahan: wrote the article.

The author declared no conflict of interest.

Kristin Eckel-Mahan is funded by NIH grants DK114037 and DK125922.