The chronobiology, etiology and pathophysiology of obesity

Abstract

The effect of CD on human health is an emerging issue. Many records link CD with diseases such as cancer, cardiovascular, cognitive impairment and obesity, all of them conducive to premature aging. The amount of sleep has declined by 1.5 h over the past century, accompanied by an important increase in obesity. Shift work, sleep deprivation and exposure to bright light at night increase the prevalence of adiposity. Animal models have shown that mice with Clock gene disruption are prone to developing obesity and MetS. This review summarizes the latest developments with regard to chronobiology and obesity, considering (1) how molecular clocks coordinate metabolism and the specific role of the adipocyte; (2) CD and its causes and pathological consequences; (3) the epidemiological evidence of obesity as a chronobiological illness; and (4) theories of circadian disruption and obesity. Energy intake and expenditure, relevance of sleep, fat intake from a circadian perspective and psychological and genetic aspects of obesity are examined. Finally, ideas about the use of chronobiology in the treatment of obesity are discussed. Such knowledge has the potential to become a valuable tool in the understanding of the relationship between the chronobiology, etiology and pathophysiology of obesity.

Figure 1

A general overview of the functional organization of the circadian system in mammals. Inputs: Environmental periodical cues can reset the phase of the central pacemaker so that the period and phase of circadian rhythms became coincident with the timing of the external cues. Central pacemakers: The SCN is considered the major pacemaker of the circadian system, driving circadian rhythmicity in other brain areas and peripheral tissues by sending them neural and humoral signals. Peripheral oscillators: Most peripheral tissues and organs contain circadian oscillators. Usually they are under the control of the SCN; however, under some circumstances (that is, restricted feeding, jet-lag and shift work.), they can desynchronize from the SCN. Outputs: Central pacemakers and peripheral oscillators are responsible for the daily rhythmicity observed in most physiological and behavioral functions. Some of these over-rhythms (physical exercise, core temperature, sleep–wake cycle and feeding time), in turn, provide a feedback, which can modify the function of SCN and peripheral oscillators. SCN, suprachiasmatic nucleus.

Figure 2

Organization of the mammalian circadian intracellular oscillator. The cellular oscillator is composed of a positive (CLOCK and BMAL1) and a negative (PER1–3 and CRY1, 2) limb. CLOCK–BMAL1 heterodimeres, through binding to E-box elements, drive the transcription of several genes: Cry1, Cry2, Per1, Per2, Per3, Rev-Erbα, Rorα and multiple CCGs. After dimerization PERs and CRYs undergo nuclear translocation inhibiting CLOCK–BMAL1-mediated transcription. Once the levels of PERs and CRYs fall, the negative repression is lifted and CLOCK–BMAL1 binds again to the E-box. A secondary stabilizing loop is established by the negative, REV-ERBα, and positive, RORα, effect on Bmal1 transcription through their activity on RORE. In addition, the PPARα, a CCG, induces Bmal1 and Rev-Erbα transcription through its action on PPAR-response elements located in their respective promoters. The molecular circadian clock in linked to metabolism through several mechanisms. RORα and Rev-Erbα regulates lipid metabolism and adipogenesis. BMAL1, brain- and muscle ANRT-like protein-1; CCG, Clock-controlled gene; CLOCK, Circadian Locomotor Output Cycles Kaput; CRY, cryptochrome circadian protein; PER, Period Circadian Protein; PPAR, peroxisome proliferator-activated receptor; REV-ERBα, erythroblastosis virus-α; RORα, retinoic acid receptor-related orphan receptor-α.

Figure 3

The causes and consequences of circadian disruption. CD is the result of a phase shift in the oscillation of the circadian (solid line) and activity-controlled physiological processes (dotted line). This circadian pathology can be induced by factors related to the following: Inputs: low contrast between day and night synchronizing signals (continuous light, frequent snacking, low physical exercise…); by Zeitgebers with different periods or unusual phasing (that is, light at night, nocturnal eating, nocturnal physical activity…) or by Zeitgeber shifts (that is, daylight-saving time, crossing time zones, shift work…). Oscillators: The uncoupling between the different oscillators inside the SCN caused by aging, the uncoupling between the central and peripheral oscillators or clock gene functional alterations result in circadian disruption. Outputs: Nocturnal melatonin suppression and loss of cortisol rhythmicity are also chronodisrupters. Many pathological states can be promoted or impaired as consequence of CD. CD, chronodisruption.

Figure 4

A schematic representation of the putative pathways leading from sleep loss to obesity and the MetS. MetS, metabolic syndrome.

Figure 5

Different strategies in the treatment of obesity from a chronobiological perspective.