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.

The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy - which are altered in standard Bmal1 knockout mice - remained unaltered, while atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, while overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt re-evaluation of the systemic consequences of disruption of the molecular clock.

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Background Genome-wide association studies (GWAS) have established ADAMTS7 as a locus for coronary artery disease (CAD) in humans. Yet, these studies fail to provide directionality for the association between ADAMTS7 and CAD. Previous reports have implicated ADAMTS7 in the regulation of vascular smooth muscle cell (VSMC) migration, but a role and direction of impact for this gene in atherogenesis has not been shown in relevant model systems. Methods and Results We bred an Adamts7 whole body knockout (KO) mouse onto both the Ldlr and Apoe KO hyperlipidemic mouse models. Adamts7−/−/Ldlr−/− and Adamts7−/−/Apoe−/− mice displayed significant reductions in lesion formation in aortas and aortic roots as compared to controls. Adamts7 KO mice also showed reduced neointimal formation after femoral wire injury. Adamts7 expression was induced in response to injury and hyperlipidemia but was absent at later timepoints, and primary Adamts7 KO VSMCs showed reduced migration in the setting of TNFα stimulation. ADAMTS7 localized to cells positive for SMC markers in human CAD lesions, and sub-cellular localization studies in cultured VSMCs placed ADAMTS7 at the cytoplasm and cell membrane, where it co-localized with markers of podosomes. Conclusions These data represent the first in vivo experimental validation of the association of Adamts7 with atherogenesis, likely through modulation of vascular cell migration and matrix in atherosclerotic lesions. These results demonstrate that Adamts7 is proatherogenic, lending directionality to the original genetic association and supporting the concept that pharmacological inhibition of ADAMTS7 should be atheroprotective in humans, making it an attractive target for novel therapeutic interventions.

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The physiology of a wide variety of organisms is organized according to periodic environmental changes imposed by the earth's rotation. This way, a large number of physiological processes present diurnal rhythms regulated by an internal timing system called the circadian clock. As part of the rhythmicity in physiology, drug efficacy and toxicity can vary with time. Studies over the past four decades present diurnal oscillations in drug absorption, distribution, metabolism, and excretion. On the other hand, diurnal variations in the availability and sensitivity of drug targets have been correlated with time-dependent changes in drug effectiveness. In this review, we provide evidence supporting the regulation of drug kinetics and dynamics by the circadian clock. We also use the examples of hypertension and cancer to show current achievements and challenges in chronopharmacology.

Isoprostanes (iPs) are prostaglandin (PG) isomers generated by free radical-catalyzed peroxidation of polyunsaturated fatty acids (PUFAs). Urinary F 2 -iPs, PGF 2␣ isomers derived from arachidonic acid (AA) are used as indices of lipid peroxidation in vivo. We now report the characterization of two major F 3 -iPs, 5-epi-8,12-iso-iPF 3␣ -VI and 8,12-iso-iPF 3␣ -VI, derived from the -3 fatty acid, eicosapentaenoic acid (EPA). Although the potential therapeutic benefits of EPA receive much attention, a shift toward a diet rich in -3 PUFAs may also predispose to enhanced lipid peroxidation. Urinary 5-epi-8,12-iso-iPF 3␣ -VI and 8,12-iso-iPF 3␣ -VI are highly correlated and unaltered by cyclooxygenase inhibition in humans. Fish oil dose-dependently elevates urinary F 3 -iPs in mice and a shift in dietary -3/-6 PUFAs is reflected by an increasing slope [m] of the line relating urinary 8, 12-iso-iPF 3␣ -VI and 8,12-iso-iPF 2␣ -VI. Administration of bacterial lipopolysaccharide evokes a reversible increase in both urinary 8,12-iso-iPF 3␣ -VI and 8,12-iso-iPF 2␣ -VI in humans on an ad lib diet. However, while excretion of the iPs is highly correlated (R 2 median ‫؍‬ 0.8), [m] varies by an order of magnitude, reflecting marked inter-individual variability in the relative peroxidation of -3 versus -6 substrates. Clustered analysis of F 2 -and F 3 -iPs refines assessment of the oxidant stress response to an inflammatory stimulus in vivo by integrating variability in dietary intake of -3/-6 PUFAs. Isoprostanes (iPs),2 a family of prostaglandin isomers, are generated initially in situ by free radical attack on polyunsaturated fatty acids (PUFAs) in cell membranes. There, they can be immunodetected and quantified by mass spectrometry (1). They are then cleaved by phospholipases (2), circulate in plasma, and are excreted in urine (3). F 2 -iPs, isomers of PGF 2␣ (3), derived from peroxidation of arachidonic acid (AA), are the most studied species. F 2 -iPs can be quantified in normal animal and human biological fluids and tissues, implying ongoing lipid peroxidation under physiological conditions, despite replete and diversified endogenous antioxidant defense systems (4). The measurement of urinary F 2 -isoprostanes has been used to reflect lipid peroxidation noninvasively in several human diseases (5-8). In addition to their utility as markers of oxidant stress (OS), high concentrations of some F 2 -iPs also possess biological activity in vitro, including bronchoconstriction (9), vasoconstriction (10), platelet aggregation (11, 12), and adhesion (13). These effects result from iPs acting as incidental ligands at prostaglandin receptors. It is unknown whether this capacity of individual iPs to ligate prostanoid receptors has relevance to the concentration of the multiple endogenous iP species likely to be formed simultaneously under conditions of oxidant stress in vivo.iPs analogous to the F 2 -iPs may be formed from other fatty acid substrates (14 -19), including the fish oil constituent, eicosapentaenoic acid (EPA) (20). Pote...

The circadian clock directs many aspects of metabolism to separate in time opposing metabolic pathways and optimize metabolic efficiency. The master circadian clock of the suprachiasmatic nucleus synchronizes to light, while environmental cues such as temperature and feeding out of phase to the light schedule may synchronize peripheral clocks. This misalignment of central and peripheral clocks may be involved in the development of disease and the acceleration of aging, possibly in a gender specific manner. Here we discuss the interplay between the circadian clock and metabolism, the importance of the microbiome and how they relate to aging.