Impairment of Peripheral Circadian Clocks Precedes Metabolic Abnormalities in ob/ob Mice

Abstract

Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of metabolic abnormalities, but the chicken-and-egg question remains unresolved. To address this issue, we investigated the cause-effect relationship in obese, diabetic ob/ob mice. Compared with control C57BL/6J mice, the daily mRNA expression profiles of the clock and clock-controlled genes Clock, Bmal1, Cry1, Per1, Per2, and Dbp were substantially dampened in the liver and adipose tissue, but not the hypothalamic suprachiasmatic nucleus, of 10-wk-old ob/ob mice. Four-week feeding of a low-calorie diet and administration of leptin over a 7-d period attenuated, to a significant and comparable extent, the observed metabolic abnormalities (obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia) in the ob/ob mice. However, only leptin treatment improved the impaired peripheral clocks. In addition, clock function, assessed by measuring levels of Per1, Per2, and Dbp mRNA at around peak times, was also reduced in the peripheral tissues of 3-wk-old ob/ob mice without any overt metabolic abnormalities. Collectively these results indicate that the impairment of peripheral clocks in ob/ob mice does not result from metabolic abnormalities but may instead be at least partially caused by leptin deficiency itself. Further studies are needed to clarify how leptin deficiency affects peripheral clocks.

Chronic mild stress alters circadian expressions of molecular clock genes in the liver

“…At 9 wk of age, they were divided into two groups, one continuously housed as stated above (control) and the other subjected to 1 wk of unpredictable CMS. At 10 wk of age, 24 mice of each strain were killed by cervical dislocation at 6-h intervals over 24 h (2,4,28,46) to obtain liver and brain samples at zeitgeber times (ZTs) 3, 9, 15, and 21 in which ZT 0 is defined as lights on and ZT 12 as lights off (n ϭ 6/group for each observation point). All animal studies were conducted in accordance with the institutional guidelines for animal experiments and were approved by Tohoku University.…”

“…The results are presented as means Ϯ SE. Two-way ANOVA followed by Bonferroni's post hoc test was used to determine variance with respect to time and mouse group (n ϭ 6 mice/observation point for each group) (2,21,26). All experiments were performed at least three times to confirm that the data presented in Figs.…”

“…Intriguingly, in all of these murine models, serum corticosterone levels were shown to be altered (1,27). In addition, circadian expressions of hepatic clock genes are impaired in young ob/ob mice even before the onset of metabolic abnormalities, and this impairment in rhythmic expressions of hepatic clock genes was restored by leptin treatment (2). Serum corticosterone levels are increased in ob/ob mice (1,52), and leptin treatment depresses corticosterone levels via suppression of the HPA axis (17).…”

Interplay between the endocrine and circadian systems in fishes

“…In vivo experiments show that leptin injection potentiates behavioural light-resetting in mice, which is accompanied by a higher induction of the clock genes Per1 and Per2 in the SCN (Mendoza et al 2011). Moreover, it has been shown that genetically obese 232:3 mice (ob/ob, leptin deficiency; db/db, lacking the leptin receptor) exhibit disturbances in their peripheral clocks (Ando et al 2011, Grosbellet et al 2016. However, the modulation of circadian clocks by leptin in fishes remains unexplored.…”

Glucose tolerance in obese men is associated with dysregulation of some angiogenesis-related gene expressions in subcutaneous adipose tissue

“…Obesity and its metabolic complications are one of the most profound public health problems and result from interactions between genes and environmental. There is data that development of obesity is connected with dysregulation of numerous gene expressions mainly through biological clock because biological rhythms are an integral component of essentially all aspects of life and regulate many physiological functions, including insulin sensitivity and cellular proliferation [4][5][6][7]. Molecular and cellular studies have demonstrated relationships between the dysfunction of circadian clocks and the development of obesity and metabolic abnormalities, including type 2 diabetes [8].…”