Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly

Metabolic crosstalk: molecular links between glycogen and lipid metabolism in obesity.

Glycogen and lipids are major storage forms of energy that are tightly regulated by hormones and metabolic signals. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen due to increased expression of the glycogenic scaffolding protein PTG/R5. PTG promoter activity was increased and glycogen levels were augmented in mice and cells after activation of the mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target SREBP1. Deletion of the PTG gene in mice prevented HFD-induced hepatic glycogen accumulation. Of note, PTG deletion also blocked hepatic steatosis in HFD-fed mice and reduced the expression of numerous lipogenic genes. Additionally, PTG deletion reduced fasting glucose and insulin levels in obese mice while improving insulin sensitivity, a result of reduced hepatic glucose output. This metabolic crosstalk was due to decreased mTORC1 and SREBP activity in PTG knockout mice or knockdown cells, suggesting a positive feedback loop in which once accumulated, glycogen stimulates the mTORC1/SREBP1 pathway to shift energy storage to lipogenesis. Together, these data reveal a previously unappreciated broad role for glycogen in the control of energy homeostasis

Sex-specific differences in hepatic steatosis in obese spontaneously hypertensive (SHROB) rats

Abstract Background Patients with metabolic syndrome, who are characterized by co-existence of insulin resistance, hypertension, hyperlipidemia, and obesity, are also prone to develop non-alcoholic fatty liver disease (NAFLD). Although the prevalence and severity of NAFLD is significantly greater in men than women, the mechanisms by which gender modulates the pathogenesis of hepatic steatosis are poorly defined. The obese spontaneously hypertensive (SHROB) rats represent an attractive model of metabolic syndrome without overt type 2 diabetes. Although pathological manifestation caused by the absence of a functional leptin receptor has been extensively studied in SHROB rats, it is unknown whether these animals elicited sex-specific differences in the development of hepatic steatosis. Methods We compared hepatic pathology in male and female SHROB rats. Additionally, we examined key biochemical and molecular parameters of signaling pathways linked with hyperinsulinemia and hyperlipidemia. Finally, using methods of quantitative polymerase chain reaction (qPCR) and western blot analysis, we quantified expression of 45 genes related to lipid biosynthesis and metabolism in the livers of male and female SHROB rats. Results We show that all SHROB rats developed hepatic steatosis that was accompanied by enhanced expression of SREBP1, SREBP2, ACC1, and FASN proteins. The livers of male rats also elicited higher induction of Pparg, Ppara, Slc2a4, Atox1, Skp1, Angptl3, and Pnpla3 mRNAs. In contrast, the livers of female SHROB rats elicited constitutively higher levels of phosphorylated JNK and AMPK and enhanced expression of Cd36. Conclusion Based on these data, we conclude that the severity of hepatic steatosis in male and female SHROB rats was mainly driven by increased de novo lipogenesis. Moreover, male and female SHROB rats also elicited differential severity of hepatic steatosis that was coupled with sex-specific differences in fatty acid transport and esterification.https://deepblue.lib.umich.edu/bitstream/2027.42/145618/1/13293_2018_Article_202.pd

Substructure in the Coma Cluster: Giants vs Dwarfs

The processes that form and shape galaxy clusters, such as infall, mergers and dynamical relaxation, tend to generate distinguishable differences between the distributions of a cluster's giant and dwarf galaxies. Thus the dynamics of dwarf galaxies in a cluster can provide valuable insights into its dynamical history. With this in mind, we look for differences between the spatial and velocity distributions of giant (b18) galaxies in the Coma cluster. Our redshift sample contains new measurements from the 2dF and WYFFOS spectrographs, making it more complete at faint magnitudes than any previously studied sample of Coma galaxies. It includes 745 cluster members - 452 giants and 293 dwarfs. We find that the line-of-sight velocity distribution of the giants is significantly non-Gaussian, but not that for the dwarfs. A battery of statistical tests of both the spatial and localised velocity distributions of the galaxies in our sample finds no strong evidence for differences between the giant and dwarf populations. These results rule out the cluster as a whole having moved significantly towards equipartition, and they are consistent with the cluster having formed via mergers between dynamically-relaxed subclusters.Comment: 23 pages, 6 figures, to appear in Ap

A comparison of the galaxy populations in the Coma and distant clusters: the evolution of k+a galaxies and the role of the intracluster medium

The spectroscopic properties of galaxies in the Coma cluster are compared with those of galaxies in rich clusters at $z \sim 0.5$, to investigate the evolution of the star formation history in clusters. Luminous galaxies with $M_V \leq -20$ and post-starburst/post-starforming (k+a) spectra which constitute a significant fraction of galaxies in distant cluster samples are absent in Coma, where spectacular cases of k+a spectra are found instead at $M_V>-18.5$ and represent a significant proportion of the cluster dwarf galaxy population. A simple inspection of their positions on the sky indicates that this type of galaxy does not show a preferential location within the cluster, but the bluest and strongest-lined group of k+a's lies in projection towards the central 1.4 Mpc of Coma and have radial velocities significantly higher than the cluster mean. We find a striking correlation between the positions of these young and strong post-starburst galaxies and substructure in the hot intracluster medium (ICM) identified from {\it XMM-Newton} data, with these galaxies lying close to the edges of two infalling substructures. This result strongly suggests that the interaction with the dense ICM could be responsible for the quenching of the star formation (thus creating the k+a spectrum), and possibly, for any previous starburst. The evolution with redshift of the luminosity distribution of k+a galaxies can be explained by a ``downsizing effect'', with the maximum luminosity/mass of actively star-forming galaxies infalling onto clusters decreasing at lower redshift. We discuss the possible physical origin of this downsizing effect and the implications of our results for current scenarios of environmental effects on the star formation in galaxies.Comment: 21 pages, 7 figures, to appear in ApJ, version after referee's change

Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice

© 2016 the American Physiological Society. We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle

Pharmacologic activation of estrogen receptor α increases mitochondrial function, energy expenditure, and brown adipose tissue

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154285/1/fsb2fj201600787rr.pd