The Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease

Abstract

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. In the following review, we will delve into what is known on the circadian rhythmicity of nutrient metabolism and discuss obesity as a circadian disease.

Keywords: circadian rhythms; metabolism; molecular clock; obesity.

Figure 1

The Circadian Transcription–Translation Feedback Loop (TTFL). (a) Positive arms of the TTFL (1) ROR binding to the RORE initiates transcription of Bmal1, Clock and Npas2, which are shuttled to the cytoplasm for translation. (2) BMAL1 and CLOCK/NPAS2 form a complex in the cytoplasm. (3) The BMAL1:CLOCK/NPAS2 complex translocates to the nucleus where it binds to E-box elements to (4) upregulate transcription of Per, Cry and Rev-erbα/β and other core clock genes; (b) Negative arms of the TTFL (1) PER and CRY form a complex that (2) translocates to the nucleus and inhibits the transcriptional activity of BMAL1::CLOCK/NPAS2. REV-ERBα/β translocates to the nucleus and represses the transcription of Bmal1, Clock and Npas2. (4) PER monomers inhibit REV-ERBα/β.

Figure 2

The Human Metabolic Clock. During the active phase, food consumption results in an increase in blood glucose that elicits an increase in glucose absorption and glycogen synthesis. Lipids are also absorbed more readily, and lipoprotein lipase (LPL) activity increases. Amino acid absorption and protein synthesis increase during active-phase food consumption. Carbohydrates are more easily metabolized during the early active phase, whereas lipids and proteins are metabolized preferentially during the late active phase. The inactive phase is characterized by an increase in catabolic processes. Glycogenolysis is upregulated and lipolysis is increased. During inactivity, glutamine synthase and autophagy pathways are upregulated. Created with BioRender.com (accessed on 28 June 2022).

Figure 3

Select Effects of Molecular Clock Knockouts. Examples of select metabolic effects arising from molecular clock knockouts. Created with BioRender.com (accessed on 28 June 2022).