Attribution of specific roles to the two ubiquitously expressed PI 3-kinase (PI3K) isoforms p110α and p110β in biological functions they have been implicated, such as in insulin signalling, has been challenging. While p110α has been demonstrated to be the principal isoform activated downstream of the insulin receptor, several studies have provided evidence for a role of p110β. Here we have used isoform-selective inhibitors to estimate the relative contribution of each of these isoforms in insulin signalling in adipocytes, which are a cell type with essential roles in regulation of metabolism at the systemic level. Consistent with previous genetic and pharmacological studies, we found that p110α is the principal isoform activated downstream of the insulin receptor under physiological conditions. p110α interaction with Ras enhanced the strength of p110α activation by insulin. However, this interaction did not account for the selectivity for p110α over p110β in insulin signalling. We also demonstrate that p110α is the principal isoform activated downstream of the β-adrenergic receptor (β-AR), another important signalling pathway in metabolic regulation, through a mechanism involving activation of the cAMP effector molecule EPAC1. This study offers further insights in the role of PI3K isoforms in the regulation of energy metabolism with implications for the therapeutic application of selective inhibitors of these isoforms.

The vascular endothelium traditionally viewed as a simple physical barrier between the circulation and tissue is now well-established as a key organ mediating whole organism homeostasis by release of a portfolio of anti-inflammatory and pro-inflammatory vasoactive molecules. Healthy endothelium releases anti-inflammatory signaling molecules such as nitric oxide and prostacyclin; in contrast, diseased endothelium secretes pro-inflammatory signals such as reactive oxygen species, endothelin-1 and tumor necrosis factor-alpha (TNFα). Endothelial dysfunction, which has now been identified as a hallmark of different components of the cardiometabolic syndrome including obesity, type 2 diabetes and hypertension, initiates and drives the progression of tissue damage in these disorders. Recently it has become apparent that, in addition to vasoactive molecules, the vascular endothelium has the potential to secrete a diverse range of small molecules and proteins mediating metabolic processes in adipose tissue (AT), liver, skeletal muscle and the pancreas. AT plays a pivotal role in orchestrating whole-body energy homeostasis and AT dysfunction, characterized by local and systemic inflammation, is central to the metabolic complications of obesity. Thus, understanding and targeting the crosstalk between the endothelium and AT may generate novel therapeutic opportunities for the cardiometabolic syndrome. Here, we provide an overview of the role of the endothelial secretome in controlling the function of AT. The endothelial-derived metabolic regulatory factors are grouped and discussed based on their physical properties and their downstream signaling effects. In addition, we focus on the therapeutic potential of these regulatory factors in treating cardiometabolic syndrome, and discuss areas of future study of potential translatable and clinical significance. The vascular endothelium is emerging as an important paracrine/endocrine organ that secretes regulatory factors in response to nutritional and environmental cues. Endothelial dysfunction may result in imbalanced secretion of these regulatory factors and contribute to the progression of AT and whole body metabolic dysfunction. As the vascular endothelium is the first responder to local nutritional changes and adipocyte-derived signals, future work elucidating the changes in the endothelial secretome is crucial to improve our understanding of the pathophysiology of cardiometabolic disease, and in aiding our development of new therapeutic strategies to treat and prevent cardiometabolic syndrome.

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota.

SummaryThere are at least two distinct types of thermogenic adipocyte in mammals: a pre-existing form established during development, termed classical brown adipocytes and an inducible form, ‘beige’ adipocytes1–3. Various environmental cues can stimulate a process frequently referred to as ‘beiging’ of white adipose tissue (WAT), leading to enhanced thermogenesis and obesity resistance 4, 5. Whilst beiging of WAT as a therapeutic goal for obesity and obesity-related complications has attracted much attention6–9; therapeutics stimulating beiging without deleterious side-effects remain elusive10. The endothelium lines all blood vessels and is therefore in close proximity to all cells. Many studies support the possibility that the endothelium acts as a paracrine organ11–14. We explored the potential role of endothelial insulin-like growth factor-1 receptor (IGF-1R) as a paracrine modulator of WAT phenotype. Here we show that a reduction in endothelial IGF-1R expression in the presence of nutrient excess leads to white adipocyte beiging, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell autonomous paracrine mechanism. We demonstrate that this is mediated by endothelial release of malonic acid, which we show, using prodrug analogues, has potentially therapeutically-relevant properties in the treatment of metabolic disease.

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This paper presents two design methods and example analysis results for low cycle fatigue design of HP/HT flowlines. The first method is based on fatigue tests and traditional S-N curves. The second method is based on fracture mechanics in accordance with the Level 2 Engineering Critical Assessment (ECA) procedure as described in the BS7910:1999 guideline [1]. Both methods utilize the same thermal load histograms developed for the flowline's service life using the ABAQUS finite element program with the expected temperature and pressure history input. The S-N curves are derived from seawater and sour service fatigue tests and are modified to reflect the fatigue behavior of a material in the low cycle and high stress range. Fracture toughness and fatigue crack growth rates are derived from tests conducted in air, seawater, and sour service environments, and are modified to reflect the effects of load frequency, load form, and stress ratio. Also provided in this paper is the calibration result between S-N fatigue constants and crack growth rate constants obtained by the fracture mechanics ECA model.The design example includes a HP/HT flowline with lateral buckles near the middle. Fatigue damage derived from the S-N approach are below the design value for a 25-year service life. The critical flaws are found to be internal surface and embedded cracks in the circumferential direction in the girth weld along the flowline. A non-destructive testing (NDT) inspection strategy is recommended. Allowable initial flaw sizes are identified for the flowline example. Flaw size sensitivity is also discussed with respect to the crack tip opening displacement (CTOD) and the total stress correction factor (TSCF).

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