Attenuating Effect of Clock Mutation on Triglyceride Contents in the ICR Mouse Liver under a High-Fat Diet

Abstract

Energy homeostasis is subjected to a circadian control that synchronizes energy intake and expenditure. The transcription factor CLOCK, a key component of the molecular circadian clock, controls many kinds of rhythms, such as those for locomotor activity, body temperature, and metabolic functions. The purpose of the present study is to understand the function of the Clock gene during lipid metabolism in the liver using Clock-mutant mice. Clock-mutant mice with an ICR background were fed a high-fat diet for 13 weeks, and liver triglyceride, serum triglyceride, and serum free fatty acid levels were examined. Triglyceride content in the liver was significantly less increased in Clock-mutant mice on a high-fat diet compared to wild-type mice on a high-fat diet. Acsl4 and Fabp1 mRNA levels in the liver showed daily rhythms in wild-type mice. In contrast, Clock -mutant mice had attenuated daily rhythms of Acsl4 and Fabp1 gene expression in the liver under both normal and high-fat diet conditions compared to wild-type mice. In Clock-mutant mice, suppression of Acsl4 and Fabp1 mRNA in the liver under high-fat diet conditions may have attenuated the accumulation of triglycerides in the liver compared to wild-type mice under the same conditions. In conclusion, the authors demonstrate that mice with a Clock mutation showed less triglyceride accumulation in the liver through the suppression of Acsl4 and Fabp1 gene expression when fed a high-fat diet compared to wild-type mice fed the same diet.

Lipidomics reveals diurnal lipid oscillations in human skeletal muscle persisting in cellular myotubes cultured in vitro

“…Importantly, all seven mammalian elongase family members are either rhythmically expressed or their expression is affected by core clock gene alterations in peripheral mouse tissues, with Elovl1, Elovl5, and Elovl6 being circadian in mouse skeletal muscle (5,12,45). Moreover, ACSL4 was shown to be rhythmic in mouse liver, and its rhythmicity was attenuated in ClockΔ19 mutant mice (46). We therefore hypothesize that enzymes involved in long chain fatty acid activation and elongation are important drivers of lipid oscillations.…”

Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals

“…Diurnal variations of lipid biosynthesis in the liver, intestine and fat tissues have been reported. Expression of genes involved in TG biosynthesis shows circadian rhythmicity (Adamovich et al, 2014;Kohsaka et al, 2007;Kudo et al, 2007;Shostak et al, 2013). For example, sterol regulatory element-binding protein (SREBP)-1c, acetyl co-A carboxylase (ACC), acyl-CoA synthetase (ACSL), fatty acid synthase (FAS) and fatty acid binding protein 4 show diurnal variations in the liver and adipose tissue of mice (Kohsaka et al, 2007;Kudo et al, 2007;Shostak et al, 2013).…”

Immunometabolism: Is it under the eye of the clock?

“…[66,116] Clock 19 Global • Obese and display impaired glucose sensitivity with insulin resistance and reduced islet size [112,113] • Increased plasma triglyceride and glucose levels [85,114] • Increased fibrotic damage in model of pulmonary fibrosis [87] • Impaired anti-oxidant defense [87] Cry1/Cry2 Global • Increased NAD+ and ATP. Decreased lactate and triglycerides in MEFs [95] • Greater inflammatory damage in CIA model [146] • Increased Cxcl1.…”

“…These mice harbor a 51-amino acid deletion in the transactivation domain of Clock, disrupting its ability to bind to other proteins including BMAL1 [111], leading to a range of metabolic dysfunctions. Clock 19 mice become obese on a high fat diet [112], insulin resistant [113], and display altered plasma triglyceride [114] and glucose levels [85].…”