Obesity as a Circadian Disease: Comparison
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Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Lauren Nicole Woodie.

Obesity and other metabolic diseases are major public health issues that are particularly prevalent in industrialized societies where circadian rhythmicity is disturbed by shift work, jet lag, and/or social obligations. In mammals, daylight entrains the hypothalamic suprachiasmatic nucleus (SCN) to a ≈24 h cycle by initiating a transcription/translation feedback loop (TTFL) of molecular clock genes. The downstream impacts of the TTFL on clock-controlled genes allow the SCN to set the rhythm for the majority of physiological, metabolic, and behavioral processes. The TTFL, however, is ubiquitous and oscillates in tissues throughout the body. Tissues outside of the SCN are entrained to other signals, such as fed/fasting state, rather than light input. This system requires a considerable amount of biological flexibility as it functions to maintain homeostasis across varying conditions contained within a 24 h day. In the face of either circadian disruption (e.g., jet lag and shift work) or an obesity-induced decrease in metabolic flexibility, this finely tuned mechanism breaks down. Indeed, both human and rodent studies have found that obesity and metabolic disease develop when endogenous circadian pacing is at odds with the external cues.

  • circadian rhythms
  • obesity
  • molecular clock
  • metabolism

1. Introduction

Obesity and metabolic diseases are among the most prevalent and costly health issues in the modern world. Obesity is strongly correlated with a wide array of serious comorbidities, such as type II diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and, most recently, COVID-19 severity [1,2,3,4,5][1][2][3][4][5]. In the United States, more than 42% of the adult population is currently considered obese [6]. Given that these comorbidities are among the leading causes of premature mortality in the world, the prevention and treatment of obesity is becoming an increasingly important public health imperative [6].
Although obesity and metabolic diseases are multifactorial in their causes and presentation, they are particularly prevalent in populations with external pressures that promote disruptions to circadian rhythmicity [7,8,9][7][8][9]. For example, the Nurses’ Health Studies, which followed more than 140,000 women over several decades to evaluate their risk for chronic diseases, revealed that those working rotating night shifts were more likely to develop metabolic diseases such as T2DM than those with more consistent work schedules [10].
Constant access to food, entertainment, shift work, and trans-time zone flights continues to push the limits of the human circadian system. The word “circadian” comes from the Latin words circa meaning “about” and dies meaning “day”; thus, a circadian rhythm is defined as a biological pattern that oscillates according to an approximately 24 h time schedule and repeats consistently without the input of external stimuli [11,12][11][12]. A number of biological processes exhibit circadian rhythmicity and work to maintain metabolic flexibility and organismal homeostasis in the varying environmental states present across a 24 h day [13,14,15,16,17][13][14][15][16][17]. The environment (i.e., food availability, light intensity, ambient temperature, etc.) and the needs of an individual within it fluctuate drastically across 24 h, necessitating a flexible metabolic system capable of adjusting quickly and effectively to external changes.
A hallmark of obesity and metabolic disease, however, is a decreased ability to adapt effectively between metabolic states [18,19,20,21][18][19][20][21]. Furthermore, when endogenous circadian pacing is at odds with the external environment, this finely tuned mechanism breaks down and has been found to be an important risk factor for a series of disease states including cardiovascular illness, substance use disorder, attention-deficit-hyperactivity disorder (ADHD), and certain psychiatric and neurodegenerative conditions such as dementia, depression, and anxiety in addition to obesity and metabolic disease [22,23,24,25,26,27,28,29,30,31][22][23][24][25][26][27][28][29][30][31].

2. Obesity as a Circadian Disease

The modern world is active for all 24 h of the day. Constant access to food, entertainment, shift work, and trans-time zone flights push the limits of human circadian physiology. The circadian system has evolved to temporally separate cellular states and promote flexibility in metabolic responses to the different environmental demands of a 24 h day (Gerhart-Hines and Lazar, 2015). However, when endogenous circadian pacing is at odds with the light:dark cycle, a myriad of health issues—collectively known as circadian time-sickness—can occur [26].
Disrupted sleep is a major contributor to circadian time-sickness and metabolic dysfunction. Indeed, just one night of sleep disturbance impairs glucose metabolism in humans [27,28,29][27][28][29]. Individuals who go to sleep later and sleep for fewer hours are more likely to be obese than people who regularly obtain a quality night’s sleep [98,99][32][33]. Decreased sleep quality and quantity also increases the risk of developing T2DM [30,31,98][30][31][32]. Sleep disturbances elevate orexin-mediated sympathetic nervous system activity, which causes elevated gluconeogenesis and can lead to glucose intolerance and insulin resistance [100][34]. Importantly, melatonin expression is constitutive and does not oscillate in a circadian manner among individuals with diabetes or obesity, further suggesting that the rhythms of sleep and metabolism are closely interconnected with one another [101,102,103,104][35][36][37][38]. It follows, then, that exogenous melatonin administration in humans can prevent weight gain, hyperglycemia, hyperinsulinemia, and hyperlipidemia [101,102,103,104][35][36][37][38].
Diet can impact circadian health even without significant alterations in sleep quantity or quality. As discussed earlier, all animals including humans alternate between periods of feeding and fasting. One of the major evolutionary theories behind the architecture of the circadian clock is that it serves to establish temporal separation between those metabolic states. This theory is supported by the breakdown of rhythmicity and metabolic flexibility, as well as the decline in overall health, that results when distinct fed/fasting states are not maintained [105][39].
In chow-fed mice, reverse-phase feeding (RPF) to the inactive phase results in elevated triglycerides, altered glucose metabolism, and weight gain when compared to TRF mice fed in their active phase [106][40]. This phenotype was exacerbated when an inactive phase shift work paradigm was coupled with RPF. Notably, however, TRF was able to correct the metabolic consequences of shift work during the inactive phase. Inactive workers on active TRF had corrected rhythms in activity, blood glucose, and triglyceride levels with significantly reduced body weight [106][40].
A 2016 study by Yasumoto et al. found that RPF also increased plasma corticosterone, insulin, and leptin levels [107][41]. At the molecular level, RPF produced phase delays or shifts in core clock genes in the liver, white adipose tissue, and skeletal muscle [107][41]. This is consistent with more recent work by Guan et al., which showed that the implementation of an RPF regime led to approximately 12 h phase shifts in the expression of core clock genes such as Reverbα/β, Bmal1, and nearly all oscillating genes in the liver [45][42]. Altogether, the close alignment between feeding patterns and circadian gene expression indicates that feeding is a crucial timekeeper for peripheral clocks such as the liver. More broadly, the metabolic consequences of RPF demonstrate that uncoupling food consumption from the body’s natural internal clock is detrimental to overall health.
A 2019 study from Panda’s group found that the liver-specific deletion of critical core clock genes such as Rev-erbα/β and Bmal1, together with whole-body knockouts of Cry1/Cry2, led to extreme and rapid weight gain in mice, once again showing that an intact circadian system is critical to the maintenance of metabolic homeostasis [92][43]. However, the implementation of TRF lessened the phenotypic consequences of missing core clock machinery. TRF mice were significantly more resistant to accruing excess weight even in the absence of these key core clock components. Broadly speaking, their findings demonstrate that the rhythms of feeding and fasting may be capable of reversing the gene expression changes caused by absent core clock elements [92][43].
Natural circadian oscillations can also mitigate the metabolic consequences associated with a high-fat diet. An SCN-specific deletion of both Rev-erbα and Rev-erbβ shifted their internal circadian clocks by around three hours; they found that double knockout mice were also significantly more vulnerable to HFD-induced weight gain than mice whose REV-ERB nuclear receptors remained intact [24]. Other studies observed a similar phenotypic effect upon deletions or mutations of core clock genes [108][44]; for example, Clock mutations altering internal mouse clocks also rendered mice more susceptible to weight gain and hyperleptinemia [109,110][45][46]. In both cases, a desynchrony between organismal endogenous clocks and environmental light cues exacerbated metabolic dysfunction. Appropriately functioning core clock machinery is therefore integral to the maintenance of metabolic homeostasis. Framed slightly differently, misalignment between circadian gene expression and external light/dark cycles hinders bodily protection against the metabolic effects of high-fat diets (such as diet-induced obesity).
While disruptions to the rhythmic expression of core clock genes leads to phenotypic changes upon exposure to a high-fat diet, the causal relationship appears to swing in both directions—that is, high-fat food consumption has also been found to alter and dampen patterns of circadian gene expression [44,47,95][47][48][49]. Indeed, the rhythmicity of Clock, Bmal1, and Per2 gene expression was significantly dampened in the liver and white adipose tissue among mice on a high-fat diet [44,47,95][47][48][49]. HFD has important ramifications regarding metabolic flexibility, making it more difficult for an organism to switch between carbohydrate and lipid metabolism [44,46,47][47][48][50]. These results combine to show that patterns of rhythmic gene expression are key mediators for a wide variety of metabolic processes. Molecular disruptions to core clock machinery appear to increase the propensity for a wide array of metabolic disease states such as obesity and T2DM. Beyond genetics, dietary choices such as a high-fat diet threaten to upend the body’s natural circadian rhythms, creating a self-reinforcing cycle of metabolic dysfunction that can have serious health consequences.

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