Dongsha Atoll is an important stepping-stone that promotes regional genetic connectivity in the South China Sea.

BACKGROUND: Understanding region-wide patterns of larval connectivity and gene flow is crucial for managing and conserving marine biodiversity. Dongsha Atoll National Park (DANP), located in the northern South China Sea (SCS), was established in 2007 to study and conserve this diverse and remote coral atoll. However, the role of Dongsha Atoll in connectivity throughout the SCS is seldom studied. In this study, we aim to evaluate the role of DANP in conserving regional marine biodiversity. METHODS: In total, 206 samples across nine marine species were collected and sequenced from Dongsha Atoll, and these data were combined with available sequence data from each of these nine species archived in the Genomic Observatories Metadatabase (GEOME). Together, these data provide the most extensive population genetic analysis of a single marine protected area. We evaluate metapopulation structure for each species by using a coalescent sampler, selecting among panmixia, stepping-stone, and island models of connectivity in a likelihood-based framework. We then completed a heuristic graph theoretical analysis based on maximum dispersal distance to get a sense of Dongsha's centrality within the SCS. RESULTS: Our dataset yielded 111 unique haplotypes across all taxa at DANP, 58% of which were not sampled elsewhere. Analysis of metapopulation structure showed that five out of nine species have strong regional connectivity across the SCS such that their gene pools are effectively panmictic (mean pelagic larval duration (PLD) = 78 days, sd = 60 days); while four species have stepping-stone metapopulation structure, indicating that larvae are exchanged primarily between nearby populations (mean PLD = 37 days, sd = 15 days). For all but one species, Dongsha was ranked within the top 15 out of 115 large reefs in the South China Sea for betweenness centrality. Thus, for most species, Dongsha Atoll provides an essential link for maintaining stepping-stone gene flow across the SCS. CONCLUSIONS: This multispecies study provides the most comprehensive examination of the role of Dongsha Atoll in marine connectivity in the South China Sea to date. Combining new and existing population genetic data for nine coral reef species in the region with a graph theoretical analysis, this study provides evidence that Dongsha Atoll is an important hub for sustaining connectivity for the majority of coral-reef species in the region.

Effectiveness of continuous versus single injection femoral nerve block for total knee arthroplasty: A double blinded, randomized trial.

BACKGROUND: Effective analgesia following total knee arthroplasty (TKA) is important for maximizing patient satisfaction, early participation in physical therapy and reducing the hospital stay. This trial compared continuous catheter femoral nerve block (cFNB) to single injection femoral nerve block (sFNB) in terms of analgesia, opioid consumption, and participation in physical therapy and associated side effects. METHODS: This randomized, double blinded trial was conducted in a non-university hospital setting, without major changes to anesthesia or surgical clinical pathways. A total of 85 patients scheduled for primary TKA were randomized to receive either cFNB (n=44) or sFNB (n=41). All patients had FNB with 0.5% ropivacaine bolus followed by subarachnoid block for surgery. Postoperatively, 0.2% ropivacaine infusion was commenced in cFNB group and a sham catheter was taped to the skin in sFNB group. All patients received a structured multimodal analgesia regimen throughout hospital stay. The primary outcomes were peak resting visual analogue scale (VAS) scores and morphine consumption at 48h postoperatively. RESULTS: VAS scores (Mean difference 0.25, 95% Confidence Interval (CI) -0.56 to 1.06; [P=0.196]) and morphine consumption (Mean difference 0.95mg, 95% CI -9.99 to 11.89; [P=0.863]) were not significantly different among patients who received cFNB versus sFNB at 48h. There was no difference in hospital stay (P=0.517) or long-term functional recovery between the two groups (P=0.385). CONCLUSIONS: sFNB block provides equal pain relief compared with cFNB, after TKA with no significant difference in opioid consumption, hospital stay, physical therapy outcomes or associated side effects.

Evidence that diet-induced hyperleptinemia, but not hypothalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice.

High-fat diet (HFD) feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/Agouti-related peptide neurons. In the current study, we investigated the time course over which this occurs and the mechanisms responsible for ghrelin resistance. After 3 weeks of HFD feeding, neither peripheral nor central ghrelin increased food intake and or activated NPY neurons as demonstrated by a lack of Fos immunoreactivity or whole-cell patch-clamp electrophysiology. Pair-feeding studies that matched HFD calorie intake with chow calorie intake show that HFD exposure does not cause ghrelin resistance independent of body weight gain. We observed increased plasma leptin in mice fed a HFD for 3 weeks and show that leptin-deficient obese ob/ob mice are still ghrelin sensitive but become ghrelin resistant when central leptin is coadministered. Moreover, ob/ob mice fed a HFD for 3 weeks remain ghrelin sensitive, and the ability of ghrelin to induce action potential firing in NPY neurons was blocked by leptin. We also examined hypothalamic gliosis in mice fed a chow diet or HFD, as well as in ob/ob mice fed a chow diet or HFD and lean controls. HFD-fed mice exhibited increased glial fibrillary acidic protein-positive cells compared with chow-fed mice, suggesting that hypothalamic gliosis may underlie ghrelin resistance. However, we also observed an increase in hypothalamic gliosis in ob/ob mice fed a HFD compared with chow-fed ob/ob and lean control mice. Because ob/ob mice fed a HFD remain ghrelin sensitive, our results suggest that hypothalamic gliosis does not underlie ghrelin resistance. Further, pair-feeding a HFD to match the calorie intake of chow-fed controls did not increase body weight gain or cause central ghrelin resistance; thus, our evidence suggests that diet-induced hyperleptinemia, rather than diet-induced hypothalamic gliosis or HFD exposure, causes ghrelin resistance.

Calorie-restricted weight loss reverses high-fat diet-induced ghrelin resistance, which contributes to rebound weight gain in a ghrelin-dependent manner.

Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons. In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss. Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls. DIO mice received chow diet ad libitum or chow diet with 40% CR. Chow-fed and high-fat-fed mice served as controls. Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin. We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression. We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point. This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus. Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss.

Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance.

In obesity, anorectic responses to leptin are diminished, giving rise to the concept of "leptin resistance." Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response. We show that mice that lack TCPTP in neuronal cells have enhanced leptin sensitivity and are resistant to high-fat-diet-induced weight gain and the development of leptin resistance. Also, intracerebroventricular administration of a TCPTP inhibitor enhances leptin signaling and responses in mice. Moreover, the combined deletion of TCPTP and PTP1B in neuronal cells has additive effects in the prevention of diet-induced obesity. Our results identify TCPTP as a critical negative regulator of hypothalamic leptin signaling and causally link elevated TCPTP to the development of cellular leptin resistance in obesity.

A recent update on the role of ghrelin in glucose homeostasis.

Recent evidence highlights an important role of ghrelin in glucose homeostasis. In this review we provide a detailed summary of recent advances in this field. We describe the effects of ghrelin on all aspects of glucose homeostasis including glucose-stimulated insulin secretion, hepatic glucose production and insulin stimulated glucose disposal in the peripheral tissues. The existing evidence suggests ghrelin primarily inhibits insulin release from the pancreas and we highlight an important mechanism involving AMPK-UCP2 ATP-stimulated potassium channels and intracellular calcium regulation. Ghrelin increases hepatic glucose production and prevents glucose disposal in muscle and adipose tissues, which collectively leads to hyperglycemia and impaired glucose tolerance. We discuss the important role ghrelin plays in glucose homeostasis during different metabolic states. During severe calorie restriction, ghrelin increases blood glucose concentrations in order to maintain glucose homeostasis. In diet-induced obesity, ghrelin exacerbates hyperglycemia and promotes a diabetic phenotype.

Metabolic status regulates ghrelin function on energy homeostasis.

Ghrelin plays an important role in energy metabolism by regulating food intake, body weight and glucose homeostasis. In this review, we highlight recent developments describing how ghrelin stimulates neuropeptide Y (NPY) neurons, but not pro-opiomelanocortin neurons, to regulate food intake. We describe a novel signaling modality, in which ghrelin activates NPY/agouti-related protein (AgRP) neurons through fatty acid oxidation, reactive oxygen species buffering and mitochondrial function. We hypothesize that this unique system may serve to maintain NPY/AgRP cell function during prolonged negative energy balance. We discuss the idea that the metabolic status plays a key role in ghrelin function. For example, our recent studies illustrate that diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. On the other side of the metabolic coin, ghrelin and GOAT knockout models show that ghrelin is required to maintain blood glucose during severe calorie restriction. We propose the hypothesis that ghrelin primarily functions during negative energy balance to maintain whole-body energy homeostasis.

Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons.

Circulating ghrelin is decreased in obesity, and peripheral ghrelin does not induce food intake in obese mice. We investigated whether ghrelin resistance was a centrally mediated phenomenon involving dysregulated neuropeptide Y (NPY) and agouti-related peptide (AgRP) circuits. We show that diet-induced obesity (DIO) (12 wk) suppresses the neuroendocrine ghrelin system by decreasing acylated and total plasma ghrelin, decreasing ghrelin and Goat mRNA in the stomach, and decreasing expression of hypothalamic GHSR. Peripheral (ip) or central (intracerebroventricular) ghrelin injection was able to induce food intake and arcuate nucleus Fos immunoreactivity in chow-fed but not high-fat diet-fed mice. DIO decreased expression of Npy and Agrp mRNA, and central ghrelin was unable to promote expression of these genes. Ghrelin did not induce AgRP or NPY secretion in hypothalamic explants from DIO mice. Injection of NPY intracerebroventricularly increased food intake in both chow-fed and high-fat diet-fed mice, indicating that downstream NPY/AgRP neural targets are intact and that defective NPY/AgRP function is a primary cause of ghrelin resistance. Ghrelin resistance in DIO is not confined to the NPY/AgRP neurons, because ghrelin did not stimulate growth hormone secretion in DIO mice. Collectively, our data suggests that DIO causes ghrelin resistance by reducing NPY/AgRP responsiveness to plasma ghrelin and suppressing the neuroendocrine ghrelin axis to limit further food intake. Ghrelin has a number of functions in the brain aside from appetite control, including cognitive function, mood regulation, and protecting against neurodegenerative diseases. Thus, central ghrelin resistance may potentiate obesity-related cognitive decline, and restoring ghrelin sensitivity may provide therapeutic outcomes for maintaining healthy aging.