Article

Obesity in mice with adipocyte-specific deletion of clock component Arntl

Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nature medicine (Impact Factor: 27.36). 11/2012; 18(12). DOI: 10.1038/nm.2979
Source: PubMed

ABSTRACT

Adipocytes store excess energy in the form of triglycerides and signal the levels of stored energy to the brain. Here we show that adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component, results in obesity in mice with a shift in the diurnal rhythm of food intake, a result that is not seen when the gene is disrupted in hepatocytes or pancreatic islets. Changes in the expression of hypothalamic neuropeptides that regulate appetite are consistent with feedback from the adipocyte to the central nervous system to time feeding behavior. Ablation of the adipocyte clock is associated with a reduced number of polyunsaturated fatty acids in adipocyte triglycerides. This difference between mutant and wild-type mice is reflected in the circulating concentrations of polyunsaturated fatty acids and nonesterified polyunsaturated fatty acids in hypothalamic neurons that regulate food intake. Thus, this study reveals a role for the adipocyte clock in the temporal organization of energy regulation, highlights timing as a modulator of the adipocyte-hypothalamic axis and shows the impact of timing of food intake on body weight.

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Available from: Georgios K Paschos
    • "It is difficult to know how these cell culture systems relate to in vivo adipose tissue development. Several groups have reported increased adiposity in mice lacking Bmal1 expression either in all cells (Lamia et al., 2008; Guo et al., 2012; Kennaway et al., 2013) or specifically in adipocytes (Paschos et al., 2012) and in Clock m/m mutant mice (Rudic et al., 2004; Shostak et al., 2013), in which exon 19 of the Clock transcript is skipped, resulting in reduced DNA binding activity (King et al., 1997). This is consistent with the increased adipogenesis observed in some studies of Bmal1 "
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    • "Mice housed under a light/dim-light cycle increased food intake ratios during the light phase gained weight and became more glucose intolerant than mice under normal light/dark cycles, despite equivalent total caloric intake and total daily activities [72]. Similarly, adipocyte-specific deletion of the Bmal1 gene increased the food intake ratio of the light phase and body weight [73•]. Ablation of the adipocyte clock altered the circulating concentration of polyunsaturated fatty acids in the hypothalamus, resulting in a change of feeding behavior. "
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    ABSTRACT: Circadian clocks that comprise clock genes exist throughout the body and control daily physiological events. The central clock that dominates activity rhythms is entrained by light/dark cycles, whereas peripheral clocks regulating local metabolic rhythms are determined by feeding/fasting cycles. Nutrients reset peripheral circadian clocks and the local clock genes control downstream metabolic processes. Metabolic states also affect the clockworks in feedback manners. Because the circadian system organizes whole energy homeostasis, including food intake, fat accumulation, and caloric expenditure, the disruption of circadian clocks leads to metabolic disorders. Recent findings show that time-restricted feeding during the active phase amplifies circadian clocks and improves metabolic disorders induced by a high-fat diet without caloric reduction, whereas unusual/irregular food intake induces various metabolic dysfunctions. Such evidence from nutrition studies that consider circadian system (chrononutrition) has rapidly accumulated. We review molecular relationships between circadian clocks and nutrition as well as recent chrononutrition findings.
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    • "These mice showed also abnormal leptin secretion, sleep disturbances, altered locomotor activity and changed rhythms of adiponectin and resistin release. Also, mice with adipose tissue-targeted deletion of BMAL1 displayed increased adiposity and body weight, impairment of feeding rhythms and alterations in the expression of hypothalamic neuropeptides that regulate appetite (Paschos et al. 2012). Similarly, obese humans were found to differ in the expression patterns of several clock and metabolic genes in adipose tissue (Garaulet et al. 2011), in the rhythms of plasma adipokines (Saad et al. 1998) and in daily rhythms of leptin and ghrelin "
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