Improved knowledge of all aspects of adipose biology will be required to counter the burgeoning epidemic of obesity. Interest in adipogenesis has increased markedly over the past few years with emphasis on the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation. Many different events contribute to the commitment of a mesenchymal stem cell to the adipocyte lineage including the coordination of a complex network of transcription factors, cofactors and signalling intermediates from numerous pathways.

Adipocyte differentiation from the inside out.

Mechanisms for insulin resistance: common threads and missing links.

Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels (approximately 50, approximately 550, approximately 750 microM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from approximately 50 to approximately 750 microM) decreased glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a reduction in glycogen synthesis and to a lesser extent (approximately 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration (approximately 750 microM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium (approximately 550 microM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by approximately 50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.

/pdf/mechanisms-of-fatty-acid-induced-inhibition-of-glucose-4174mdqw81.pdf

Mechanisms of fatty acid-induced inhibition of glucose uptake.

https://www.cell.com/cell/pdf/S0092-8674(05)01277-8.pdf

The Many Faces of PPARγ

Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages: commitment of mesenchymal stem cells to a preadipocyte fate and terminal differentiation. Cell shape and extracellular matrix remodelling have recently been found to regulate preadipocyte commitment and competency by modulating WNT and RHO-family GTPase signalling cascades. Adipogenic stimuli induce terminal differentiation in committed preadipocytes through the epigenomic activation of peroxisome proliferator-activated receptor-γ (PPARγ). The coordination of PPARγ with CCAAT/enhancer-binding protein (C/EBP) transcription factors maintains adipocyte gene expression. Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally.

/pdf/forming-functional-fat-a-growing-understanding-of-adipocyte-34ef2038x4.pdf

Forming functional fat: a growing understanding of adipocyte differentiation

Adipose triglyceride lipase (ATGL) is a recently described adipose-enriched protein with triglyceride-specific lipase activity. ATGL shares the greatest sequence homology with adiponutrin, a nutritionally regulated protein of unclear biological function. Here we present a functional analysis of ATGL and adiponutrin and describe their regulation by insulin. Retroviral-mediated overexpression of ATGL in 3T3-L1 adipocytes increased basal and isoproterenol-stimulated glycerol and nonesterified fatty acid (NEFA) release, whereas siRNA-mediated knockdown of ATGL had the opposite effect. In contrast, siRNA-mediated knockdown of adiponutrin in 3T3-L1 adipocytes had no effect on glycerol or NEFA release. In mice, both ATGL and adiponutrin are nutritionally regulated in adipose tissue, with ATGL being upregulated and adiponutrin being downregulated by fasting. In 3T3-L1 adipocytes, insulin decreased ATGL and increased adiponutrin expression in a dose- and time-dependent manner, suggesting that insulin directly mediates this nutritional regulation. In addition, adipose expression of ATGL was increased by insulin deficiency and decreased by insulin replacement in streptozotocin-induced diabetic mice and was increased in fat-specific insulin receptor knockout mice, whereas adiponutrin showed the opposite pattern. These data suggest that murine ATGL but not adiponutrin contributes to net adipocyte lipolysis and that ATGL and adiponutrin are oppositely regulated by insulin both in vitro and in vivo.

http://www.kershawlab.pitt.edu/Kershaw2006.pdf

Adipose Triglyceride Lipase Function, Regulation by Insulin, and Comparison With Adiponutrin

Overexpression of APOBEC-1 Results in Mooring Sequence-dependent Promiscuous RNA Editing (∗)

Editing the apolipoprotein B (apoB) RNA involves deamination of cytidine by the catalytic subunit, APOBEC-1, as a component of an editosome. A tripartite sequence (editing motif) is essential for editosome assembly and site-specific editing. Current theory for the regulation of apoB RNA editing proposes that APOBEC-1 is rate limiting in cells and determines the proportion of edited apoB mRNAs. An evaluation of how the overexpression of APOBEC-1 increased the proportion of edited RNAs has led to the discovery of a paradox. McArdle cells edit a constant proportion of apoB RNA regardless of the total number of apoB RNAs expressed. Despite virtually identical editing motifs, apoB RNA transcripts from the endogenous gene and transfected, exogenous cDNA were edited with characteristic, but different efficiencies. This suggested that these RNAs were interacting with the editing machinery as distinct and noncompeting populations. We evaluated whether the presence of introns in the endogenous transcript may have distinguished it as a distinct population having reduced editing efficiency. The editing efficiency of chimeric splicing-editing RNA substrates was highest on fully processed RNA. Increased exon length improved utilization of the editing motif in these chimeric constructs. Taken together, the data suggest that the close proximity of introns can reduce apoB RNA editing efficiency. A population "gating" hypothesis is proposed wherein the proportion of edited RNAs in a population is determined my multiple cis- and trans-acting factors as RNAs pass through a nuclear restriction point.

Determinants involved in regulating the proportion of edited apolipoprotein B RNAs.

Erratum: Regulated production of a peroxisome proliferator-activated receptor-γ ligand during an early phase of adipocyte differentiation in 3T3-L1 adipocytes (Journal of Biological Chemistry (2004) 279 (36093-36102))

Regulated production of a peroxisome proliferator-activated receptor-γ ligand during an early phase of adipocyte differentiation in 3T3-L1 adipocytes

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