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Volume 32 | February 2020

BMP4 gene therapy enhances insulin sensitivity but not adipose tissue browningOne of the early and central events in white adipocyte commitment is the action of bone morphogenetic protein 4 (BMP4). Overexpression or gene therapy with BMP4 can protect from obesity. Hoffmann and colleagues tested whether BMP4 gene therapy can also be used to treat already established obesity. Their results show that obesity is not reduced but that BMP4 improves whole-body insulin sensitivity, enhances insulin signaling in all key metabolic tissues, and reduces key gluconeogenic enzymes in the liver despite no weight loss.

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The carbohydrate-insulin model does not explain the impact of macronutrients on body weightThe carbohydrate-insulin model (CIM) suggests that high levels of dietary carbohydrates elevate insulin secretion, which suppresses fatty acid oxidation and the release of fatty acids from adipose tissue while promoting lipogenesis. This creates a state of cellular “internal starvation” that drives both increased food intake and decreased energy expenditure, leading to obesity. Hu et al. directly tested specific predictions of the CIM in a mouse model. They found that only the changes in the post-prandial insulin and fasting glucose followed the CIM’s predictions in relation to the dietary carbohydrate. Fasting insulin, energy intake, energy expenditure, and body fat mass did not follow the trends predicted by the CIM.

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Pharmacological antagonism of the incretin system protects against obesityThe incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1), are gut-derived peptides released in response to ingested nutrients that mediate important actions on nutrient metabolism. GLP-1 receptor agonists have been developed for the treatment of obesity independent of type 2 diabetes. Paradoxically, Glp1r-/- mice are protected against diet-induced obesity. Svendsen et al. hypothesized that developmental compensations might be present in animals with germ-line deletions of the incretin receptors. Therefore, they used acute pharmacologic antagonism in fully developed animals, but still found decreases in body weight under a high fat diet.

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Regulation of muscle and metabolic physiology by hypothalamic EPOAlthough erythropoietin (EPO) is a glycoprotein hormone that is essential for erythropoiesis, it has been shown to influence nonhematopoietic tissues and may impact body weight and glucose control. Apart from its peripheral production and actions, limited evidence exists showing that EPO or its receptor (EpoR) could be detected in the brain. Wang et al. observed that the hypothalamus is a key site for the production and action of neural EPO. They also found that brain EPO decreases with aging and dietary obesity. Hypothalamic EPO treatment in aging or obesity offered benefits in muscle protection as well as in metabolic protection against energy and glucose imbalance.

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Fasting induces remodeling of the orexigenic projections from the ARC to the PVHNeuronal populations of the hypothalamic arcuate nucleus (ARC) regulate food intake. ARC neurons strongly innervate the hypothalamic paraventricular nucleus (PVH), and these ARC-PVH projections are recognized as key regulators of food intake. Cabral, Fernandez, et al. provide neuroanatomical and functional evidence indicating that ARC-PVH projections undergo major morphological remodeling under fasting conditions, and growth hormone secretagogue receptor signaling is required for these effects.

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SWI/SNF complex subunit BAF60a represses hepatic ureagenesisHepatic ureagenesis plays a predominant role in maintaining nitrogen and ammonia homeostasis in mammals. Disruption of ureagenesis leads to hyperammonemia, accompanied by hepatic encephalopathy and liver fibrosis. BAF60a is a subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) complexes that regulates a series of metabolic pathways as a transcription factor. Zhang, Dong, et al. have elucidated a BAF60a-orchestrated upstream regulatory mechanism in the urea cycle and provide a mechanism through which steatotic hepatocytes produce ammonia via formation of a BAF60a-YB-1 complex.

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Hepatic ERα accounts for sex differences in the ability to cope with excess dietary lipidsIn female mammals, liver estrogen receptor alpha (ERα) plays a central role in the adaptive response of hepatic metabolism to the energy requirements characterizing the different reproductive stages. Unlike in females, the expression of ERα in the adult male liver is very low. Although obesity is prevalent in females, fertile women are to some extent protected from obesity-associated fatty liver and cardio-metabolic disease, suggesting the involvement of estrogen signaling. Meda and colleagues highlight the essential role of hepatic ERα in the regulation of lipid metabolism in the liver of the two sexes when dietary lipids are in excess. In males, hepatic ERα action contributes to liver lipid accumulation; conversely, in females, ERα prevents the hepatic lipid deposition.

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Single-cell ATAC-Seq in human pancreatic islets reveals T2D regulatory signaturesGenetic predisposition is one of the factors that can lead to type 2 diabetes (T2D). ATAC-seq is a high-throughput epigenomic profiling method to determine chromatin accessibility across samples in a tissue-wide manner. Rai, Quang, et al. use single-cell combinatorial indexing ATAC-seq that enables them to deconvolve cell populations and identify cell-type-specific regulatory signatures underlying T2D. They found T2D single nucleotide polymorphisms to be significantly enriched in beta cell-specific and across cell-type shared islet open chromatin, but not in alpha or delta cell-specific open chromatin. They also developed a novel deep learning-based strategy to improve signal recovery and feature reconstruction for low abundance cell populations and apply it successfully to delta cells (<5% of the total islet population) identified in the study.

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Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injuryReperfusion after cerebral ischemic insult is necessary for survival. However, it is associated with the induction of oxidative stress and inflammatory responses, leading to reperfusion injury. This can drive extensive tissue damage and increase the risk of sepsis and multiple organ failure. Cordes and colleagues tested itaconate as a possible protector from reperfusion injury. They found that in mouse models, itaconate reduced oxidative stress and improved cerebral hemodynamics, inflammation, neurological function, and survival.

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mTORC1 restrains adipocyte lipolysisThe mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that nucleates two structurally and functionally distinct complexes, mTORC1 and mTORC2. The available data do not identify a clear or consistent role for adipocyte mTORC1 signaling in systemic lipid homeostasis. Paolella et al. demonstrate that mTORC1 signaling in adipose tissue is critical for the maintenance of plasma lipid homeostasis in the fed state. Lack of mTORC1 in adipocytes increases both lipolysis and circulating triglycerides in fed mice.

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Continuous glucose monitoring reveals glycemic variability and hypoglycemia after VSG in ratsWith the rising use of bariatric surgery, there is also greater awareness of associated complications, one of which is post-bariatric surgery hypoglycemia (PBH). Episodes of hypoglycemia impair cognition and increase the risk for syncope, cardiac arrhythmias, seizures, coma, and even death. While medication or lifestyle modifications can be used effectively to reduce recurrence in diabetic patients, this is not the case for bariatric surgery patients. Evers, Kim, and colleagues propose that rat models of VSG replicate many aspects of PBH in humans. They found that VSG increases glycemic variability, and in response to a mixed-meal liquid gavage, hypoglycemia is readily detectable. Blockade of GLP-1R signaling prevents falls in the glucose nadir but does not improve glycemic variability.

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Leptin receptor sequences crucial for the STAT3-Independent control of metabolismLeptin, a peptide hormone produced by white adipose tissue in proportion to energy stores, plays a central role in the control of feeding and energy balance. Leptin receptor (LepRb) mainly signals trough activation of signal transducer and activator of transcription 3 (STAT3); however, there is also a second, yet unidentified signal. Barnes et al. used CRISPR/Cas9-mediated mutagenesis to generate a panel of mouse lines containing truncations of LepRb. By studying these five novel mouse lines, they identified a region of the intracellular LepRb that is required to mediate the second signal and additionally found a region that mediates a previously undescribed LepRb inhibitory signal.

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Glucocorticoid induces β cell dysfunction by involving riborepressor GAS5 LincRNAGlucocorticoid (GC) therapy may have metabolic side effects, one of which is diabetes mellitus. In GC signaling, the non-coding RNA growth arrest-specific 5 (GAS5) acts as a riborepressor by directly interacting with the glucocorticoid receptor in a dexamethasone-dependent manner. However, the role of GAS5 in human pancreatic beta cell function has not been previously addressed. Esguerra et al. demonstrate the involvement of GAS5 in GC-mediated beta cell dysfunction. Modulation of GAS5 in the human beta cell alleviated the GC-induced insulin secretion defect, demonstrating the potential of this non-coding RNA as a novel therapeutic target in countering GC-mediated beta cell dysfunction.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

Watch the most recent interview by clicking the video still. The link "referring article" directs you to this author's publication.



Ulf Smith, John Grünberg, Tobias Kroon
Sahlgrenska Academy, University of Gothenburg, Sweden
Referring article

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