Adipose tissue is essential for whole-body glucose homeostasis, with a primary role in lipid storage. It has been previously observed that lactate production is also an important metabolic feature of ...adipocytes, but its relationship to adipose and whole-body glucose disposal remains unclear. Therefore, using a combination of metabolic labeling techniques, here we closely examined lactate production of cultured and primary mammalian adipocytes. Insulin treatment increased glucose uptake and conversion to lactate, with the latter responding more to insulin than did other metabolic fates of glucose. However, lactate production did not just serve as a mechanism to dispose of excess glucose, because we also observed that lactate production in adipocytes did not solely depend on glucose availability and even occurred independently of glucose metabolism. This suggests that lactate production is prioritized in adipocytes. Furthermore, knocking down lactate dehydrogenase specifically in the fat body of Drosophila flies lowered circulating lactate and improved whole-body glucose disposal. These results emphasize that lactate production is an additional metabolic role of adipose tissue beyond lipid storage and release.
Skeletal muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance, specifically in these tissues, we leveraged the ...metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin action. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin resistance. The A/J strain, in particular, exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.
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•Gene-by-environment interactions drive tissue insulin action•Adipose insulin resistance is dissociated from systemic insulin resistance•Large adipocytes strongly associate with adipose insulin resistance•Muscle insulin resistance correlates with hyperinsulinemia and decreased glycolysis
Using a diverse panel of mouse strains, Nelson et al. reveal that muscle insulin resistance is most closely linked to levels of circulating insulin and muscle glycolytic enzymes. Intriguingly, certain strains had enlarged fat cells and adipose insulin resistance, but completely healthy muscle insulin response, showing tissue-specific progression toward metabolic disease.
Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades ...to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride–glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in Drosophila flies in vivo. Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism.
Child growth faltering persists in sub-Saharan Africa despite the scale-up of nutrition, water, and sanitation interventions over the past 2 decades. High temperatures have been hypothesised to ...contribute to child growth faltering via an adaptive response to heat, reduced appetite, and the energetic cost of thermoregulation. We did a cross-sectional study to assess whether child growth faltering is related to environmental temperature in sub-Saharan Africa.
Data were extracted from 52 Demographic and Heath Surveys, dating from 2003 to 2016, that recorded anthropometric data in children aged 0–5 years, and were linked with remotely sensed monthly mean daytime land surface temperature for 2000–16. The odds of stunting (low height-for-age), wasting (low weight-for-height), and underweight (low weight-for-age) relative to monthly mean daytime land surface temperature were determined using multivariable logistic regression.
The study population comprised 656 107 children resident in 373 012 households. Monthly mean daytime land surface temperature above 35°C was associated with increases in the odds of wasting (odds ratio 1·27, 95% CI 1·16–1·38; p<0·0001), underweight (1·09, 1·02–1·16; p=0·0073), and concurrent stunting with wasting (1·23, 1·07–1·41; p=0·0037), but a reduction in stunting (0·90, 0·85–0·96; p=0·00047) compared with a monthly mean daytime land surface temperature of less than 30°C.
Children living in hotter parts of sub-Saharan Africa are more likely to be wasted, underweight, and concurrently stunted and wasted, but less likely to be stunted, than in cooler areas. Studies are needed to further investigate the relationship between temperature and child growth, including whether there is a direct effect not mediated by food security, regional wealth, and other environmental variables. Rising temperature, linked to anthropogenic climate change, might increase child growth faltering in sub-Saharan Africa.
UK Medical Research Council and UK Global Challenges Research Fund.
Adipose tissue is essential for whole-body glucose homeostasis, with a primary role in lipid storage. It has been previously observed that lactate production is also an important metabolic feature of ...adipocytes, but its relationship to adipose and whole-body glucose disposal remains unclear. Therefore, using a combination of metabolic labeling techniques, here we closely examined lactate production of cultured and primary mammalian adipocytes. Insulin treatment increased glucose uptake and conversion to lactate, with the latter responding more to insulin than did other metabolic fates of glucose. However, lactate production did not just serve as a mechanism to dispose of excess glucose, because we also observed that lactate production in adipocytes did not solely depend on glucose availability and even occurred independently of glucose metabolism. This suggests that lactate production is prioritized in adipocytes. Furthermore, knocking down lactate dehydrogenase specifically in the fat body of Drosophila flies lowered circulating lactate and improved whole-body glucose disposal. These results emphasize that lactate production is an additional metabolic role of adipose tissue beyond lipid storage and release.
Biased G protein-coupled receptor (GPCR) ligands, which preferentially activate G protein or β-arrestin signaling pathways, are leading to the development of drugs with superior efficacy and reduced ...side effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer's disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated β-arrestin signaling modulates amyloid-β (Aβ) generation
and that
deficiency ameliorates Aβ pathology
. However,
-deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein signaling. Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated β-arrestin signaling
. In contrast to
-deficient mice, G protein-biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein-biased signaling reduces soluble Aβ levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical
AD mouse model. The changes in amyloid pathology are accompanied by robust microglial and astrocytic hypertrophy, which suggest a protective glial response that may limit amyloid plaque development in G protein-biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and β-arrestin signaling produce discrete and separable effects and provide proof of concept for the development of safer GPCR-targeting therapeutics with more directed pharmacological action for AD.
The Thinking Healthy Programme (THP), which is endorsed by WHO, is an evidence-based intervention for perinatal depression. We adapted THP for delivery by volunteer peers (laywomen from the ...community) to address the human resource needs in bridging the treatment gap, and we aimed to assess its effectiveness and cost-effectiveness in Rawalpindi, Pakistan.
In this cluster randomised controlled trial, we randomly assigned 40 village clusters (1:1) to provide either THP peer-delivered (THPP) and enhanced usual care (EUC; intervention group) or EUC only (control group) to the participants within clusters. These villages were randomly selected from eligible villages by an independent researcher. The participants were pregnant women aged 18 years or older who had scored at least 10 on the Patient Health Questionnaire-9 (PHQ-9), who we recruited from households within communities in Rawalpindi, Pakistan. The research teams who were responsible for recruiting trial participants were masked to treatment allocations. Participants attended follow-up visits at 3 and 6 months after childbirth. The primary outcomes were the severity of depressive symptoms (assessed by PHQ-9 score) and the prevalence of remission (defined as a PHQ-9 score of less than 5) in participants with available data 6 months after childbirth, which was assessed by researchers who were masked to treatment allocations. We analysed outcomes by intention to treat, adjusting for covariates that were defined a priori or that showed imbalance at baseline. The trial was registered with ClinicalTrials.gov, number NCT02111915.
Between April 15 and July 30, 2014, we randomly selected 40 of 46 eligible village clusters for assessment, as per sample size calculations. Between Oct 15, 2014, and Feb 25, 2016, we identified and screened 971 women from 20 village clusters that had been randomly assigned to the THPP and EUC group and 939 women from 20 village clusters that had been randomly assigned to the EUC only group. In the intervention group, 79 women were ineligible for inclusion, 11 women refused screening, 597 women screened negative on the PHQ-9, and one woman did not consent to participate. In the control group, 75 women were ineligible for inclusion, 14 women refused screening, 562 women screened negative on the PHQ-9, and one woman did not consent to participate. We enrolled 283 (29%) women in the intervention group and 287 (31%) women in the control group. At 6 months after childbirth, 227 (80%) women in the THPP and EUC group and 226 (79%) women in the EUC only group were assessed for the primary outcome. The severity of depression (assessed by PHQ-9 scores; standardised mean difference -0·13, 95% CI -0·31 to 0·06; p=0·07) and prevalence of remission (49% in the intervention group vs 45% in the control group; prevalence ratio 1·12, 95% CI 0·95 to 1·29; p=0·14) did not significantly differ between the groups 6 months after childbirth. There was no evidence of significant differences in serious adverse events between the groups.
THPP had no effect on symptom severity or remission from perinatal depression at 6 months after childbirth, but we found that it was beneficial on some other metrics of severity and disability and that it was cost-effective. THPP could be a step towards use of an unused human resource to address the treatment gap in perinatal depression.
National Institute of Mental Health (USA).
Background
The interest and adoption of transanal total mesorectal excision (TaTME) is growing amongst the colorectal surgical community, but there is no clear guidance on the optimal training ...framework to ensure safe practice for this novel operation. The aim of this study was to establish a consensus on a detailed structured training curriculum for TaTME.
Methods
A consensus process to agree on the framework of the TaTME training curriculum was conducted, seeking views of 207 surgeons across 18 different countries, including 52 international experts in the field of TaTME. The process consisted of surveying potential learners of this technique, an international experts workshop and a final expert’s consensus to draw an agreement on essential elements of the curriculum.
Results
Appropriate case selection was strongly recommended, and TaTME should be offered to patients with mid and low rectal cancers, but not proximal rectal cancers. Pre-requisites to learn TaTME should include completion of training and accreditation in laparoscopic colorectal surgery, with prior experience in transanal surgery. Ideally, two surgeons should undergo training together in centres with high volume for rectal cancer surgery. Mentorship and multidisciplinary training were the two most important aspects of the curriculum, which should also include online modules and simulated training for purse-string suturing. Mentors should have performed at least 20 TaTME cases and be experienced in laparoscopic training. Reviewing the specimens’ quality, clinical outcome data and entering data into a registry were recommended. Assessment should be an integral part of the curriculum using Global Assessment Scales, as formative assessment to promote learning and competency assessment tool as summative assessment.
Conclusions
A detailed framework for a structured TaTME training curriculum has been proposed. It encompasses various training modalities and assessment, as well as having the potential to provide quality control and future research initiatives for this novel technique.
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