Circadian rhythm disturbances are observed in, e.g., aging and neurodegenerative diseases and are associated with an increased incidence of obesity and diabetes. We subjected male C57Bl/6J mice to constant light [12-h light-light (LL) cycle] to examine the effects of a disturbed circadian rhythm on energy metabolism and insulin sensitivity. In vivo electrophysiological recordings in the central pacemaker of the suprachiasmatic nuclei (SCN) revealed an immediate reduction in rhythm amplitude, stabilizing at 44% of normal amplitude values after 4 d LL. Food intake was increased (+26%) and energy expenditure decreased (-13%), and we observed immediate body weight gain (d 4: +2.4%, d 14: +5.0%). Mixed model analysis revealed that weight gain developed more rapidly in response to LL as compared to high fat. After 4 wk in LL, the circadian pattern in feeding and energy expenditure was completely lost, despite continuing low-amplitude rhythms in the SCN and in behavior, whereas weight gain had stabilized. Hyperinsulinemic-euglycemic clamp analysis revealed complete abolishment of normal circadian variation in insulin sensitivity in LL. In conclusion, a reduction in amplitude of the SCN, to values previously observed in aged mice, is sufficient to induce a complete loss of circadian rhythms in energy metabolism and insulin sensitivity.

Disturbances in the circadian system are associated with the development of type 2 diabetes mellitus. Here, we studied the direct contribution of the suprachiasmatic nucleus (SCN), the central pacemaker in the circadian system, in the development of insulin resistance. Exclusive bilateral SCN lesions in male C57Bl/6J mice, as verified by immunochemistry, showed a small but significant increase in body weight (+17%), which was accounted for by an increase in fat mass. In contrast, mice with collateral damage to the ventromedial hypothalamus and paraventricular nucleus showed severe obesity and insulin resistance. Mice with exclusive SCN ablation revealed a loss of circadian rhythm in activity, oxygen consumption, and food intake. Hyperinsulinemic–euglycemic clamp analysis 8 weeks after lesioning showed that the glucose infusion rate was significantly lower in SCN lesioned mice compared with sham-operated mice (−63%). Although insulin potently inhibited endogenous glucose production (−84%), this was greatly reduced in SCN lesioned mice (−7%), indicating severe hepatic insulin resistance. Our data show that SCN malfunctioning plays an important role in the disturbance of energy balance and suggest that an absence of central clock activity, in a genetically intact animal, may lead to the development of insulin resistance.

Aims/hypothesisWhite adipose tissue (WAT) consists of various depots with different adipocyte functionality and immune cell composition. Knowledge of WAT-depot-specific differences in expandability and immune cell influx during the development of obesity is limited, therefore we aimed to characterise different WAT depots during the development of obesity in mice.MethodsGonadal WAT (gWAT), subcutaneous WAT (sWAT) and mesenteric WAT (mWAT) were isolated from male C57Bl/6J mice with different body weights (approximately 25–60 g) and analysed. Linear and non-linear regression models were used to describe the extent of WAT depot expandability and immune cell composition as a function of body weight.ResultsWhereas mouse sWAT and mWAT continued to expand with body weight, gWAT expanded mainly during the initial phase of body weight gain. The expansion diminished after the mice reached a body weight of around 40 g. From this point on, gWAT crown-like structure formation, liver steatosis and insulin resistance occurred. Mouse WAT depots showed major differences in immune cell composition: gWAT consisted mainly of macrophages, whereas sWAT and mWAT primarily contained lymphocytes.Conclusions/interpretationMarked inter-depot differences exist in WAT immune cell composition and expandability. The limited storage capacity of gWAT seems to direct the development of metabolic disorders in male C57Bl/6J mice.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3594-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

ScopeMannan oligosaccharides (MOS) have proven effective at improving growth performance, while also reducing hyperlipidemia and inflammation. As atherosclerosis is accelerated both by hyperlipidemia and inflammation, we aim to determine the effect of dietary MOS on atherosclerosis development in hyperlipidemic ApoE*3‐Leiden.CETP (E3L.CETP) mice, a well‐established model for human‐like lipoprotein metabolism.Methods and resultsFemale E3L.CETP mice were fed a high‐cholesterol diet, with or without 1% MOS for 14 weeks. MOS substantially decreased atherosclerotic lesions up to 54%, as assessed in the valve area of the aortic root. In blood, IL‐1RA, monocyte subtypes, lipids, and bile acids (BAs) were not affected by MOS. Gut microbiota composition was determined using 16S rRNA gene sequencing and MOS increased the abundance of cecal Bacteroides ovatus. MOS did not affect fecal excretion of cholesterol, but increased fecal BAs as well as butyrate in cecum as determined by gas chromatography mass spectrometry.ConclusionMOS decreased the onset of atherosclerosis development via lowering of plasma cholesterol levels. These effects were accompanied by increased cecal butyrate and fecal excretion of BAs, presumably mediated via interactions of MOS with the gut microbiota.

Heemskerk MM, van den Berg SA, Pronk AC, van Klinken JB, Boon MR, Havekes LM, Rensen PC, Willems van Dijk K, van Harmelen V. Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B. Am J Physiol Endocrinol Metab 306: E808 -E813, 2014. First published January 28, 2014; doi:10.1152/ajpendo.00641.2013.-The lipid-lowering effect of niacin has been attributed to the inhibition of cAMP production in adipocytes, thereby inhibiting intracellular lipolysis and release of nonesterified fatty acids (NEFA) to the circulation. However, long-term niacin treatment leads to a normalization of plasma NEFA levels and induces insulin resistance, for which the underlying mechanisms are poorly understood. The current study addressed the effects of long-term niacin treatment on insulin-mediated inhibition of adipocyte lipolysis and focused on the regulation of cAMP levels. APOE*3-Leiden.CETP transgenic mice treated with niacin for 15 wk were subjected to an insulin tolerance test and showed whole body insulin resistance. Similarly, adipocytes isolated from niacin-treated mice were insulin resistant and, interestingly, exhibited an increased response to cAMP stimulation by 8Br-cAMP, ␤1-and ␤2-adrenergic stimulation. Gene expression analysis of the insulin and ␤-adrenergic pathways in adipose tissue indicated that all genes were downregulated, including the gene encoding the cAMPdegrading enzyme phosphodiesterase 3B (PDE3B). In line with this, we showed that insulin induced a lower PDE3B response in adipocytes isolated from niacin-treated mice. Inhibiting PDE3B with cilostazol increased lipolytic responsiveness to cAMP stimulation in adipocytes. These data show that long-term niacin treatment leads to a downregulation of PDE3B in adipocytes, which could explain part of the observed insulin resistance and the increased responsiveness to cAMP stimulation. adipose tissue; lipolysis; adenosine 3=,5=-cyclic monophosphate; phosphodiesterases NIACIN, ALSO KNOWN AS VITAMIN B 3 , is required for the synthesis of the cofactor nicotinamide adenine dinucleotide and is therefore essential for oxidative phosphorylation in energy metabolism (8). It has been used for more than 50 years for the treatment of dyslipidemias, since it decreases plasma triglycerides, low-density lipoprotein-cholesterol, and hepatic very low density lipoprotein (VLDL) triglyceride production (25), in addition to increasing high-density lipoprotein-cholesterol. Supplementation with niacin was shown to decrease risk of cardiovascular disease and atherosclerosis in dyslipidemic humans (1) and in dyslipidemic mouse models (23), using the APOE*3-Leiden.CETP cholesteryl ester transfer protein (CETP) transgenic female mouse.The molecular mechanism by which niacin conveys its lipid-lowering effects is mostly unknown. The receptor for niacin, HCA 2 (formerly known as GPR109A), has been shown to play an important role in acute antilipolytic effects (21) (10), but is not required for the long-t...