Circadian Rhythms in Obesity and Metabolic Syndrome

Circadian rhythms are governed by a series of regulatory oscillators expressed in the suprachiasmatic nucleus (SCN), and elsewhere in the CNS as well as in most peripheral tissues, that oscillate with an approximate 24-hour periodicity usually entrained to the light-dark cycle.¹ In mice, Clock (Circadian Locomotor Output Cycles Kaput - OMIM 601851) encodes an 855 aa transcription factor involved in this process. Overexpression of Clock shortens period length. Expression of an A to T nucleotide transversion in a splice donor site that leads to exon skipping and deletion of 51 aa results in 1-hour lengthening of locomotor activity in the heterozygous state and 3- to 4-hour increase in periodicity and dampening of the amplitude of circadian rhythms, leading to loss of periodicity (arrhythmia) in the homozygous animal maintained in constant darkness. Stimulated by the observation that reduced forms of the nicotinamide adenine dinucleotide (NAD) cofactors enhance, and oxidized forms inhibit, DNA binding of the Clock transcript, Turek et al investigated the relationship between circadian rhythmicity and intermediary metabolism in homozygous Clock mutant mice (C^-/-) maintained on a 12-hour light-dark cycle. They demonstrated that relative to wild-type (WT) mice, the C^-/- mice had decreased locomotor activity during darkness. Also, the C^-/- animals ate rather evenly through the 24-hour period, whereas the WT mouse ate 3-fold more during darkness than during light. In addition, the C^-/- mice expended 10% less energy per 24 hours than did the WT animals. C^-/- animals were heavier than WT animals by 6 weeks of age; between 6-16 weeks of age, C^-/- mice ate greater amounts of food and gained more weight than did WT mice, whether ingesting a normal or high-fat diet. At 7 to 8 months of age, C^-/- animals had higher concentrations of leptin, glucose, cholesterol, and triglycerides than did WT mice, but they had similar levels of insulin. Histologically, there were hypertrophy of adipocytes and excessive glycogen and lipid within liver cells (steatosis) in C^-/- animals. In the mediobasal hypothalamus, the diurnal patterns of expression (mRNA levels) of orexin and ghrelin (orexigenic agents) and of CART (cocaine- and amphetamine-regulated transcript—an anorexigenic agent) were decreased in C^-/- mice relative to WT animals. The authors concluded that Clock and the circadian rhythms it controls have regulatory effects on energy intake and expenditure and fuel metabolism. When altered, the resultant abnormalities lead to a syndrome of obesity, hyperglycemia, and hyperlipidemia that mimics the metabolic syndrome and that might be mediated through hypothalamic pathways that regulate appetite and energy utilization.

Altered diurnal rhythms in locomotor activity, feeding, and metabolic rate in Clock mutant mice. (A) Activity counts over the 24-hour cycle during light (unshaded) and dark (shaded) periods ( B ) Diurnal rhythm of locomotor activity for mice in (A). Total activity over the 24-hour period was similar between wild-type (WT) and Clock mutant (CL) genotypes. ( C ) Diurnal rhythm of food intake. Results shown are average food intake during light and dark periods as a percentage of total food intake (*P <0.001).( D )Diurnal rhythm of metabolic rate. Results shown are average metabolic rates during the light and dark periods as a percentage of total metabolic rate. All results shown are expressed as group means ± SEM.

Editor’s Comment: Circadian rhythms are present not only in neurons within the SCN but also in single cells in most peripheral tissues and utilize the same regulatory mechanisms found in the SCN.² Thus, it is likely that the SCN synchronizes overall diurnal rhythms, while local oscillators regulate tissue-specific circadian function. It is unclear whether the metabolic effects of the described loss-of-function mutation in Clock are exerted through the SCN or in peripheral tissues, but the results of loss of diurnal variability on lipid and carbohydrate metabolism are striking. In volunteer human males, sleep deprivation lowered leptin and increased ghrelin values leading to increase in hunger and appetite.³ Future studies evaluating the role of the sleep-wake cycle on intermediary metabolism and the genesis of the metabolic syndrome in man are clearly warranted.

	www.GGHjournal.com	Return to Orginal Format
Table of Contents 21-4 Circadian Rhythms in Obesity and Metabolic Syndrome
Volume 21, Issue 4, December 2005 © 2005 Prime Health Consultants, Inc.

Circadian rhythms are governed by a series of regulatory oscillators expressed in the suprachiasmatic nucleus (SCN), and elsewhere in the CNS as well as in most peripheral tissues, that oscillate with an approximate 24-hour periodicity usually entrained to the light-dark cycle.¹ In mice, Clock (Circadian Locomotor Output Cycles Kaput - OMIM 601851) encodes an 855 aa transcription factor involved in this process. Overexpression of Clock shortens period length. Expression of an A to T nucleotide transversion in a splice donor site that leads to exon skipping and deletion of 51 aa results in 1-hour lengthening of locomotor activity in the heterozygous state and 3- to 4-hour increase in periodicity and dampening of the amplitude of circadian rhythms, leading to loss of periodicity (arrhythmia) in the homozygous animal maintained in constant darkness. Stimulated by the observation that reduced forms of the nicotinamide adenine dinucleotide (NAD) cofactors enhance, and oxidized forms inhibit, DNA binding of the Clock transcript, Turek et al investigated the relationship between circadian rhythmicity and intermediary metabolism in homozygous Clock mutant mice (C^-/-) maintained on a 12-hour light-dark cycle. They demonstrated that relative to wild-type (WT) mice, the C^-/- mice had decreased locomotor activity during darkness. Also, the C^-/- animals ate rather evenly through the 24-hour period, whereas the WT mouse ate 3-fold more during darkness than during light. In addition, the C^-/- mice expended 10% less energy per 24 hours than did the WT animals. C^-/- animals were heavier than WT animals by 6 weeks of age; between 6-16 weeks of age, C^-/- mice ate greater amounts of food and gained more weight than did WT mice, whether ingesting a normal or high-fat diet. At 7 to 8 months of age, C^-/- animals had higher concentrations of leptin, glucose, cholesterol, and triglycerides than did WT mice, but they had similar levels of insulin. Histologically, there were hypertrophy of adipocytes and excessive glycogen and lipid within liver cells (steatosis) in C^-/- animals. In the mediobasal hypothalamus, the diurnal patterns of expression (mRNA levels) of orexin and ghrelin (orexigenic agents) and of CART (cocaine- and amphetamine-regulated transcript—an anorexigenic agent) were decreased in C^-/- mice relative to WT animals. The authors concluded that Clock and the circadian rhythms it controls have regulatory effects on energy intake and expenditure and fuel metabolism. When altered, the resultant abnormalities lead to a syndrome of obesity, hyperglycemia, and hyperlipidemia that mimics the metabolic syndrome and that might be mediated through hypothalamic pathways that regulate appetite and energy utilization. Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005;308:1043–1045. Altered diurnal rhythms in locomotor activity, feeding, and metabolic rate in Clock mutant mice. (A) Activity counts over the 24-hour cycle during light (unshaded) and dark (shaded) periods ( B ) Diurnal rhythm of locomotor activity for mice in (A). Total activity over the 24-hour period was similar between wild-type (WT) and Clock mutant (CL) genotypes. ( C ) Diurnal rhythm of food intake. Results shown are average food intake during light and dark periods as a percentage of total food intake (P <0.001).( D )Diurnal rhythm of metabolic rate. Results shown are average metabolic rates during the light and dark periods as a percentage of total metabolic rate. All results shown are expressed as group means ± SEM. Reprinted with permission from Turek FW, et al. Science. 2005;308:1043–1045. Copyright © 2004 AAAS. All rights reserved. Editor’s Comment:* Circadian rhythms are present not only in neurons within the SCN but also in single cells in most peripheral tissues and utilize the same regulatory mechanisms found in the SCN.² Thus, it is likely that the SCN synchronizes overall diurnal rhythms, while local oscillators regulate tissue-specific circadian function. It is unclear whether the metabolic effects of the described loss-of-function mutation in Clock are exerted through the SCN or in peripheral tissues, but the results of loss of diurnal variability on lipid and carbohydrate metabolism are striking. In volunteer human males, sleep deprivation lowered leptin and increased ghrelin values leading to increase in hunger and appetite.³ Future studies evaluating the role of the sleep-wake cycle on intermediary metabolism and the genesis of the metabolic syndrome in man are clearly warranted. Allen W. Root, MD References - (linked to ) Rivkees S. Growth Genet Hormon. 2002;18:1–6. Block G. Sci Aging Knowl Environ. 2005;19:pe13. Spiegel K, Tasali E, Penev P, Van Cauter E. Ann Intern Med. 2004;141:846–850.