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Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles
The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals.
- Chris G. Faulkes
- , Thomas R. Eykyn
- & Dunja Aksentijevic
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Article
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Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver
The liver is segregated into spatially organized areas that serve distinct functions, though how these zones are patterned remains unclear. Here they show that mTORC1 controls spatial segregation of liver metabolic functions via modulation of Wnt signaling, and find that impaired zonation is also observed in pigs given total parenteral nutrition.
- Ana Belén Plata-Gómez
- , Lucía de Prado-Rivas
- & Alejo Efeyan
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Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape
Adipose tissue (AT) inflammation is strongly associated with obesity and constitutes an obesogenic memory upon weight loss. Here, the authors show that intermittent fasting leads to an adipocyte p53-signaling dependent emergence of lipid-associated macrophages in visceral AT of obese mice which limits the systemic fasting response.
- Isabel Reinisch
- , Helene Michenthaler
- & Andreas Prokesch
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Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R.
- Camilla Lund
- , Pablo Ranea-Robles
- & Christoffer Clemmensen
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Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice
The mechanism by which central secretin regulates metabolism is unclear. Here, the authors show that ventromedial hypothalamus-derived secretin maintains energy and bone homeostasis by controlling food intake and sympathetic nerve activity.
- Fengwei Zhang
- , Wei Qiao
- & Billy Kwok Chong Chow
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Article
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Upregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate
The origin of brain palmitic acid (PAM) has been debated. Here, by using natural abundance carbon isotope ratios and RNA sequencing the authors show that the majority of brain PAM is maintained by hepatic PAM synthesis from dietary sugars during development and is upregulated in mice fed low PAM.
- Mackenzie E. Smith
- , Chuck T. Chen
- & Richard P. Bazinet
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Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila
Dietary methionine restriction extends lifespans in many organisms. Here, the authors show in Drosophila that methionine restriction in early adulthood can increase lifespan and that the beneficial effect of the dietary manipulation declines with age.
- Hina Kosakamoto
- , Fumiaki Obata
- & Masayuki Miura
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A distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila
Plasticity in tissue function and morphology is shaped by adaptive responses to nutrient changes. Here, the authors found that a putative calibration of acyl-CoA and acetyl-CoA metabolism through ACBP6 is crucial for Drosophila intestine’s proliferative homeostasis in response to nutrient changes.
- Xiaotong Li
- & Jason Karpac
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Article
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Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization
Adiponectin is a widely studied secretory protein produced by adipocytes. Here, the authors show that adiponectin is also expressed in the kidney where it is a major driver of fatty acid oxidation, from which the kidney derives energy for gluconeogenesis.
- Toshiharu Onodera
- , May-Yun Wang
- & Philipp E. Scherer
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Article
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TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
Mitochondrial dynamics affect the thermogenic capacity of brown adipose tissue. Here, the authors show that TMEM135 regulates thermogenesis and energy homeostasis by mediating mitochondrial fission in brown adipocytes.
- Donghua Hu
- , Min Tan
- & Irfan J. Lodhi
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Article
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Deficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome
Endothelial Sirtuin1 downregulation in metabolic disorders causes vascular dysfunction and inflammation. Here, the authors show that deficiency of endothelial Sirtuin1, while having deleterious effects on the vasculature, stimulates skeletal muscle insulin sensitivity and improves glucose disposal.
- Qiuxia Li
- , Quanjiang Zhang
- & Kaikobad Irani
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Article
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The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice
Interorgan communications play key roles in the regulation of whole-body energy metabolism. Here, the authors report the myokine Musclin as a negative regulator of beige adipose thermogenesis and systemic energy homeostasis through Tfr1/PKA signalling mediated muscle fat crosstalk.
- Lu Jin
- , Shuang Han
- & Zhuo-Xian Meng
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Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice
Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Here, Park et al. identify LETMD1 as a mitochondrial matrix protein enriched in brown adipose tissue (BAT) and reveal a crucial role for it in maintaining brown adipocyte mitochondrial OXPHOS and thermogenesis upon cold stimulus.
- Anna Park
- , Kwang-eun Kim
- & Jae Myoung Suh
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Excessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P
Selenium and copper are two essential trace elements whose homeostasis and distribution is regulated by hepatic release of selenoprotein P (SELENOP) and ceruloplasmin, respectively. Here, the authors show that excessive copper results in hepatic SELENOP accumulation in the trans Golgi which might limit the selenium transport to peripheral organs.
- Maria Schwarz
- , Caroline E. Meyer
- & Anna P. Kipp
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Structural mechanism of intracellular autoregulation of zinc uptake in ZIP transporters
Zinc uptake and regulation are vital in all life forms. Here, authors describe a dimer of a ZIP-family zinc transporter in an inward-facing, inhibited conformation. A built-in zinc sensor is proposed to sense the intracellular zinc content to autoregulate zinc uptake across membranes.
- Changxu Pang
- , Jin Chai
- & Qun Liu
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Article
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Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways
Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.
- Yulong Gong
- , Bingyuan Yang
- & Wenbiao Chen
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A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation
TPC2 is an important organellar Na+/Ca2+ release channel which regulates function of lysosomes and lysosome-related organelles. Here, Wang et al. demonstrate that a gain-of-function mutation (R210C) in TPC2 leads to hypopigmentaion, enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification.
- Qiaochu Wang
- , Zengge Wang
- & Wei Li
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Article
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Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice
SUMOylation is a mechanism of posttranslational modification involved in eukaryotic cell homeostasis. Here the authors report that mice unable to control SUMOylation in the adrenal cortex develop a selective defect in glucocorticoid production due to disrupted differentiation of cells involved in steroid hormone synthesis.
- Damien Dufour
- , Typhanie Dumontet
- & Antoine Martinez
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Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice
Dysregulation of the post-translational modification neddylation has been implicated in liver diseases such as fibrosis and hepatocellular carcinoma. Here the authors report that hepatic neddylation deficiency via genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1) causes acute liver failure due to mitochondrial dysfunction and aberrant activation of NF-κB-inducing kinase in mice.
- Cheng Xu
- , Hongyi Zhou
- & Weiqin Chen
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A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience
Environmental temperature changes can alter cell membrane lipid composition but the mechanisms underlying this conserved mechanism are unclear. Here, the authors identify the megaprotein LPD-3 in C. elegans as critical for normal phospholipid distribution and cold resilience.
- Changnan Wang
- , Bingying Wang
- & Dengke K. Ma
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Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function
Diabetes is characterized by loss or dysfunction of pancreatic β-cells. Here the authors show that the signalling protein WNT4 is heterogeneously activated by β-cells during their postnatal maturation with WNT4 positive cells being more mature, and that inactivating WNT4 in β-cells after maturation impairs beta-cell function.
- Keiichi Katsumoto
- , Siham Yennek
- & Anne Grapin-Botton
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The hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans
The hypoxia response pathway can counter pathological damage caused by low oxygen availability. Here the authors employ a multiomics approach to show how the pathway reprograms metabolism towards gluconeogenesis to combat oxidative stress.
- Mehul Vora
- , Stephanie M. Pyonteck
- & Christopher Rongo
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Nanoscale segregation of channel and barrier claudins enables paracellular ion flux
Meshworks of claudin polymers control the paracellular transport and barrier properties of epithelial tight junctions. Here, the authors show different claudin nanoscale organization principles, finding that claudin segregation enables barrier formation and paracellular ion flux across tight junctions.
- Hannes Gonschior
- , Christopher Schmied
- & Martin Lehmann
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Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons
Strategies to improve cold resistance are of potential biomedical interest. Here the authors demonstrate that ferritin-mediated detoxification of iron, preventing the generation of reactive oxygen species, promotes cold survival in both Caenorhabditis elegans and cultured mammalian neurons.
- Tina Pekec
- , Jarosław Lewandowski
- & Rafal Ciosk
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Iron mobilization during lactation reduces oxygen stores in a diving mammal
Here, the authors show that Weddell seal mothers mobilize endogenous iron stores during lactation to provide to pups, resulting in iron concentrations in milk 100x higher than terrestrial mammals. This was associated with reduced dive durations in the mother, a cost of reproduction.
- Michelle R. Shero
- , Amy L. Kirkham
- & Jennifer M. Burns
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A temperature-regulated circuit for feeding behavior
Feeding behavior is modulated by ambient temperature, as lower temperatures increase the necessity for energy intake and vice versa. Here the authors identify neuronal pathways that control feeding in a temperature-dependent manner.
- Shaowen Qian
- , Sumei Yan
- & Yi Zhou
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Tight junction channel regulation by interclaudin interference
Tight junctions are formed by claudin proteins that can be classified as pore- or barrier-forming. Here, Shashikanth et al. report a third function, termed interclaudin interference, in which one claudin inhibits pore function of another claudin by disrupting its polymeric complexes.
- Nitesh Shashikanth
- , Marion M. France
- & Jerrold R. Turner
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Pancreatic α and β cells are globally phase-locked
The Ca2+ modulated pulsatile glucagon and insulin secretions by pancreatic α and β cells are critical in glucose homeostasis. Here the authors show that the Ca2+ oscillations of α and β cells are phase-locked, and that the oscillation pattern is tuned by paracrine interactions between α and β cells.
- Huixia Ren
- , Yanjun Li
- & Chao Tang
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Article
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Triiodothyronine (T3) promotes brown fat hyperplasia via thyroid hormone receptor α mediated adipocyte progenitor cell proliferation
Thyroid hormone (TH) action regulates brown adipose tissue thermogenic capacity through incompletely understood mechanisms. Here the authors report that T3, the active form of TH, increases thermogenic capacity via thyroid hormone receptor α-mediated hyperplasia of brown adipose tissue adipocyte progenitor cells.
- Shengnan Liu
- , Siyi Shen
- & Hao Ying
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Article
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Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle
The anti-aging intervention calorie restriction (CR) is thought to act via the nutrient-sensing multiprotein complex mTORC1. Here the authors show that the mTORC1-inhibitor rapamycin and CR use largely distinct mechanisms to slow mouse muscle aging.
- Daniel J. Ham
- , Anastasiya Börsch
- & Markus A. Rüegg
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Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength
Mitochondrial function is important for muscle maintenance and function, and mitochondrial proteolysis maintains mitochondrial integrity and function. Here the authors report that that loss of LONP1-dependent mitochondrial proteolysis in muscle causes reduced muscle mass and strength via activation of autophagy.
- Zhisheng Xu
- , Tingting Fu
- & Zhenji Gan
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Article
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Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.
- Susheel K. Gunasekar
- , Litao Xie
- & Rajan Sah
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The gut hormone Allatostatin C/Somatostatin regulates food intake and metabolic homeostasis under nutrient stress
Intestinal nutrient-sensing is important in metabolic control. Here the authors show that the gut-derived hormone Allatostatin C, a somatostatin homolog in fruit flies, links enteric nutrient sensing to behavioral and metabolic adaptations that maintain energetic homeostasis in Drosophila melanogaster.
- Olga Kubrak
- , Takashi Koyama
- & Kim Rewitz
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Quantitative modelling of amino acid transport and homeostasis in mammalian cells
Cytosolic amino acid concentrations are carefully maintained, but how homeostasis occurs is unclear. Here, the authors show that amino acid transporters primarily determine intracellular amino acid levels and develop a model that predicts a perturbation response similar to experimental data.
- Gregory Gauthier-Coles
- , Jade Vennitti
- & Stefan Bröer
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The enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals
Inositol hexakisphosphate kinase (IP6K) is involved in diverse cellular signalling pathways, but the physiological roles of IP6K in vivo remain unknown in mammals. Here, the authors show that the enzymatic activity of IP6K is essential for phosphate regulation in vivo.
- Yusuke Moritoh
- , Shin-ichi Abe
- & Masanori Watanabe
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Article
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Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy
Iron is essential during pregnancy for embryo and placental development and maternal health. However, in this study using mouse models, the authors demonstrate that excess maternal iron causes adverse embryo outcomes in pregnancies with underlying systemic inflammation.
- Allison L. Fisher
- , Veena Sangkhae
- & Elizabeta Nemeth
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Article
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Gut microbiota mediate the FGF21 adaptive stress response to chronic dietary protein-restriction in mice
Dietary protein restriction induces a hepatic stress response mediated by the endocrine molecule FGF21, which triggers host adaptive pathways. Here the authors demonstrate that the gut microbiome is required to trigger the FGF21 response and can be manipulated through dietary fiber supplementation.
- Anthony Martin
- , Gertrude Ecklu-Mensah
- & Suzanne Devkota
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| Open Access
IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion
Mediators of insulin signalling are targets of cullin-RING ubiquitin ligases (CRL) that mediate protein degradation, but the role of protein degradation in insulin signalling is incompletely understood. Here, the authors identified a glucose-responsive CRL4-COP1-ETV5 proteolytic axis that promotes insulin secretion, and is inhibited under hypoglycemia.
- Hong Lin
- , Yuan Yan
- & Feng Rao
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Article
| Open Access
Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis
Beige and brown fat may influence systemic metabolism through secreted signals. Here the authors identify a panel of metabolites secreted from beige and brown fat cells, which signal to influence fat tissue and skeletal muscle metabolism and have anti-obesity effects in mouse models of obesity and diabetes.
- Anna Whitehead
- , Fynn N. Krause
- & Lee D. Roberts
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Article
| Open Access
Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
The physiological role of GDF15 remains poorly defined. Here, the authors show that circulating GDF15 increases in response to prolonged exercise, but that this exercise-induced GDF15, unlike pharmacological GDF15, does not affect post-exercise food intake or exercise motivation.
- Anders B. Klein
- , Trine S. Nicolaisen
- & Christoffer Clemmensen
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Article
| Open Access
Distinct CCK-positive SFO neurons are involved in persistent or transient suppression of water intake
Water intake is critical to our life, and the subfornical organ in the brain involved in the control of this behavior. Here, the authors reveal that two distinct groups of CCK-producing neurons in the SFO suppress water intake according to the physiological condition or water-intake stimulus.
- Takashi Matsuda
- , Takeshi Y. Hiyama
- & Masaharu Noda
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Article
| Open Access
Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS
Noncoding transcripts contribute to the adaptation of cellular processes to oxygen levels. Here the authors characterize a hypoxia responsive lncRNA lincNORS and show that it has a role in cellular sterol homeostasis.
- Xue Wu
- , Cristina M. Niculite
- & Mircea Ivan
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Article
| Open Access
Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis
Bone marrow adipose tissue (BMAT) comprises over 10% of total fat mass but its systemic metabolic role is unclear. Here, the authors show that BMAT glucose uptake is not insulin or cold responsive; however, BMAT basal glucose uptake is higher than in white adipose tissue or skeletal muscle, underscoring BMAT’s potential to influence systemic glucose homeostasis.
- Karla J. Suchacki
- , Adriana A. S. Tavares
- & William P. Cawthorn
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Article
| Open Access
Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution
Dietary protein dilution, where protein is reduced and replaced by other nutrient sources without caloric restriction, promotes metabolic health via the hepatokine Fgf21. Here, the authors show that essential amino acids threonine and tryptophan are necessary and sufficient to induce these effects.
- Yann W. Yap
- , Patricia M. Rusu
- & Adam J. Rose
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Article
| Open Access
The kallikrein–kinin pathway as a mechanism for auto-control of brown adipose tissue activity
Brown adipose tissue, known produce heat by metabolizing fat, is also secretes molecules capable of communicating with other organs. Here the authors show that brown adipose tissue secretes kininogen, a component of heat system regulation, that provides auto-regulatory inhibitory signaling in brown adipose tissue.
- Marion Peyrou
- , Rubén Cereijo
- & Francesc Villarroya
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Article
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TrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits
The TrkB receptor is known to regulate obesity via appetite control, but the underlying neural circuits are not known. Here, the authors show that selective modulation of TrkB+ neurons in the paraventricular hypothalamus regulates food intake via circuits to ventromedial hypothalamus and lateral parabrachial nucleus.
- Juan Ji An
- , Clint E. Kinney
- & Baoji Xu
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Article
| Open Access
Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth
Changes in body mass index (BMI) during infancy and childhood follow a well-characterized pattern. Here, Helgeland et al. perform genome-wide association studies for BMI at 12 time points between birth and 8 years of age and find transient associations at the LEP and LEPR loci.
- Øyvind Helgeland
- , Marc Vaudel
- & Pål Rasmus Njølstad
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Article
| Open Access
A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion
The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the Drosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.
- Michael J. Texada
- , Anne F. Jørgensen
- & Kim F. Rewitz
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Article
| Open Access
Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons
Reduction in food intake elicits neuroendocrine adaptations to counterregulate the negative energy balance, e.g. via reduction in leptin levels. Here, the authors identify an additional starvation signal, growth hormone (GH). Blocking GH receptor attenuates the fall of whole body energy expenditure during food deprivation in mice.
- Isadora C. Furigo
- , Pryscila D. S. Teixeira
- & J. Donato Jr
Acinar to β-like cell conversion through inhibition of focal adhesion kinase