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


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,
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    • "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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    ABSTRACT: Circadian clocks optimize the timing of physiological processes in synchrony with daily recurring and therefore predictable changes in the environment. Until the late 1990s, circadian clocks were thought to exist only in the central nervous systems of animals; elegant studies in cultured fibroblasts and using genetically encoded reporters in Drosophila melanogaster and in mice showed that clocks are ubiquitous and cell autonomous. These findings inspired investigations of the advantages construed by enabling each organ to independently adjust its function to the time of day. Studies of rhythmic gene expression in several organs suggested that peripheral organ clocks might play an important role in optimizing metabolic physiology by synchronizing tissue-intrinsic metabolic processes to cycles of nutrient availability and energy requirements. The effects of clock disruption in liver, pancreas, muscle, and adipose tissues support that hypothesis. Adipose tissues coordinate energy storage and utilization and modulate behavior and the physiology of other organs by secreting hormones known as "adipokines." Due to behavior- and environment-driven diurnal variations in supply and demand for chemical and thermal energy, adipose tissues might represent an important peripheral location for coordinating circadian energy balance (intake, storage, and utilization) over the whole organism. Given the complexity of adipose cell types and depots, the sensitivity of adipose tissue biology to age and diet composition, and the plethora of known and yet-to-be-discovered adipokines and lipokines, we have just begun to scratch the surface of understanding the role of circadian clocks in adipose tissues. © 2015 The Author(s).
    Journal of Biological Rhythms 04/2015; 30(5). DOI:10.1177/0748730415581234 · 2.77 Impact Factor
    • "Skin adipose tissue, a thin, finely structured layer of white adipocytes , lies below the dermis and marks the innermost boundary of the skin (Fig. 1). While fibroblasts have been a model cell type of choice for in vitro circadian studies for over a decade (Balsalobre et al., 1998), and extensive work has been performed on the circadian biology of adipocytes, especially as it relates to endocrine and metabolic functions (Guo et al., 2012; Paschos et al., 2012; reviewed in Shostak et al., 2013a; Shostak et al., 2013b), specific inquiries into the role of the clock in cutaneous fibroblasts and adipocytes are lacking. What we currently know is that circadian genes are expressed in at least a subset of cells in the skin dermis and adipose tissue (Lin et al., 2009; Plikus et al., 2013). "
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    ABSTRACT: Historically, work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as the liver, fat, and muscle. In recent years, skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, and carcinogenesis. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration: the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell type-specific circadian mutants. Also, due to the accessibility of skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar ultraviolet (UV) radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it also represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. Skin also provides opportunities to interrogate the clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model for investigating the role of the clock in seasonal organismal behaviors. © 2015 The Author(s).
    Journal of Biological Rhythms 01/2015; 30(3). DOI:10.1177/0748730414563537 · 2.77 Impact Factor
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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.
    09/2014; 3(3):204-212. DOI:10.1007/s13668-014-0082-6
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