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Volume 20 | February 2019

A dual Ucp1 reporter mouse modelBrown adipose tissue (BAT) is a specialized thermogenic organ that dissipates chemical energy as heat. Brown adipocytes are equipped with uncoupling protein 1 (UCP1). UCP1 catalyzes the net transport of protons and mediates the acceleration of nutrient combustion to increase heat production. However, our knowledge of Ucp1 expression remains incomplete. Furthermore, in the search of compounds modulating transcriptional control of Ucp1, a bona fide reporter system is needed. Wang et al. generated an Ucp1-Luciferase-T2A-iRFP713-T2A knock-in mouse model to report endogenous Ucp1 expression. Taking advantage of the model, they reveal a sex specific difference in browning propensity, identify a new Ucp1 expressing adipose tissue depot, and test molecules with the potential to recruit thermogenic adipocytes.

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Preadipocytes display gender-specific bioenergetic responses Obesity is characterized by reduced mitochondrial function in several tissues including white adipose tissue (WAT). Gender differences of lipid metabolism reflected on the cellular level have been described. Keuper and colleagues determined the bioenergetic profile of preadipocytes and adipocytes from female and male donors. They found that preadipocytes retain gender differences in vitro, and cells from obese women possess a higher metabolic flexibility involving oxidative metabolism. Metabolic flexibility may assist to sustain metabolic health better as age- and BMI-matched men.

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Deletion of myeloid IRS2 enhances adipose tissue function and limits obesityMacrophages sit at the core of obesity-associated inflammation. Insulin receptor substrate 2 (IRS2) signaling in macrophages may mediate divergent biological outputs, but to date, the precise balance of such effects in metabolic physiology is unknown. Rached and colleagues generated mice with myeloid-restricted deletion of Irs2. Macrophages from these animals showed a broad anti-inflammatory phenotype when exposed to inflammatory mediators. Furthermore, these animals showed improved insulin sensitivity and a resistance to weight gain on a high fat diet associated with increased brown adipose tissue function and increased white adipose tissue browning at ambient temperature.

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GIP analogs promote body weight lowering through GIPR agonism not antagonismGastric inhibitory polypeptide (GIP), despite its role as a physiological incretin, has failed to advance as a therapeutic agent. The role of GIP to regulate systemic metabolism beyond its direct effect at the endocrine pancreas remains controversial and confusing. Body weight improvements in mice have been attributed to both GIP agonism and antagonism. To specifically address this dichotomy, Mroz et al. systematically investigated the impact of acute and chronic treatment of non-diabetic, genetically wild-type, diet-induced obese mice with GIPR agonists. Their data substantiate GIPR agonism and not antagonism to promote body weight loss in obese rodents.

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Predicting the response to short-term intensive insulin therapy for type 2 diabetesShort-term intensive insulin therapy (IIT) administered early in the course of type 2 diabetes acutely improves beta-cell function by eliminating glucotoxicity and lipotoxicity. However, this beneficial effect is not seen in all patients. Nunez Lopez et al. have generated an accurate multimodal random forests classifier using serum miRNAs with potential clinical utility for predicting responses to short-term IIT among patients with recently diagnosed type 2 diabetes.

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Regulation of glucose uptake and inflammation markers by FOXO1 and FOXO3Skeletal muscle is the main insulin-sensitive tissue for postprandial glucose disposal and for the oxidation of glucose- and lipid-based fuels. Forkhead box (FOXO) proteins play a role in the regulation of energy metabolism. However, the role of specific FOXO isoforms in metabolic homeostasis in skeletal muscle remains unclear. Lundell et al. reveal that FOXO1 and FOXO3 transcriptional activity is necessary for the regulation of glucose handling and control of inflammatory signaling in mature skeletal muscle.

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CX3CL1-Fc treatment prevents atherosclerosis The development of atherosclerotic plaques involves blood monocytes expressing the surface protein CX3CR1 binding to blood vessel endothelial cells-expressing mCX3CL1. Riopel et al. investigated the effects of administration of a long acting CX3CL1, tethered to the mouse Fc fragment (CX3CL1-Fc). They find that CX3CL1-Fc decreases monocyte adhesion to the endothelium both in vitro and in vivo. Moreover, they also demonstrate that CX3CL1-Fc treatment reduced atherosclerosis in hypercholesterolemic Ldlr KO mice without changes in plasma cholesterol levels.

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Metformin intervention prevents cardiac dysfunction in adult congenital heart diseasePatients with adult congenital heart disease (ACHD) have a higher risk of developing progressive cardiac dysfunction. Not much is currently known about how ACHD predisposes patients to heart failure upon metabolic stress. Using genetically predisposed mice and diet as a cardiac stressor, Wilmanns, Pandey, and colleagues describe a preexisting imbalance in the metabolic state of ACHD hearts. The interaction between genetic and metabolic factors ultimately leads to the clinical presentation of heart failure in ACHD. Modulation of energy utilization by Metformin, a drug widely used to treat type 2 diabetes, prevents cardiac dysfunction in the ACHD/obesity model and could therefore be considered a preventive intervention for heart failure in ACHD.

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Natural helix 9 mutants of PPARγ affect its transcriptional activityThe nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, maintenance, and function. Loss-of-function mutations in the PPARG gene cause familial partial lipodystrophy subtype 3 (FPLD3), characterized by progressive and gradual change of subcutaneous adipose tissue distribution during the peripubertal phase. Broekema et al. have identified and characterized a novel PPARγ L451P mutant in a family affected by FPLD3. They show that this mutant significantly impairs the transcriptional activity of PPARγ due to a range of molecular defects.

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Molecular signatures of diet-induced NASH and its regulation by the hepatokine TsukushiNonalcoholic steatohepatitis (NASH) greatly increases the risk for end-stage liver disease. Despite this, no effective therapeutic interventions are currently available for treating NASH, underscoring the urgent need to better understand the etiology and the progressive nature of NASH pathogenesis. In this study, Xiong and colleagues performed RNA-sequencing and quantitative proteomic analyses to elucidate the landscape of transcriptome and proteome reprogramming in NASH. They show that plasma levels of the hepatokine Tsukushi are tightly linked to NASH pathologies and that its inactivation powerfully attenuates diet-induced NASH pathogenesis.

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Hepatic c-Jun regulates glucose metabolism via FGF21 and modulates body temperature c-Jun, a prominent member of the activator protein 1 family, is involved in various physiological processes such as cell death and survival. However, the role of hepatic c-Jun in whole-body metabolism is poorly understood. Xiao, Guo, and colleagues found that hepatic c-Jun regulates glucose metabolism via fibroblast growth factor 21 and modulates body temperature through neural signaling. This study provides new insights into the crosstalk between different tissues in the regulation of whole-body metabolism and the transcriptional regulation of FGF21.

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IGF-1 corrects neuronal metabolism in sensory neurons in type 1 diabetesIndividuals with diabetes often suffer from diabetic sensorimotor polyneuropathy. In type 1 and type 2 diabetes, the level of available insulin-like growth factor-1 (IGF-1) in serum is substantially decreased. Thus, impaired neurotrophic support by insulin signaling and insulin-like growth factors have been proposed to contribute to neurodegeneration in diabetes. Aghanoori et al. reveal that IGF-1 signaling augments the AMP-activated protein kinase pathway to drive nerve repair. Specific targeting of the IGF-1 signaling axis in neurons could offer an alternative or complementary approach to treating neurological disease.

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Mitochondrial DRP1 translocation in response to glucose is impaired in altered hypothalamic glucose sensingObesity and type II diabetes result in dysregulation of energy balance. A transient cerebral hyperglycemia leads to a rapid peak of insulin secretion, which requires an upstream event involving reactive oxygen species (ROS) production and mitochondrial dynamics. Desmoulins et al. show that glucose-induced dynamin-related protein 1 (DRP1) translocation to mitochondria and ROS production in the mediobasal hypothalamus is compromised in rats fed a high fat high sugar diet for a short period of time. Therefore, alteration of hypothalamic glucose sensing-induced insulin secretion might be an early event in type II diabetes development.

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GLP-1 modulates the SuM-LH neurocircuit to control ingestive and motivated behavior Excessive food intake, especially of palatable calorically dense foods, is implicated to be the major culprit behind weight gain. It has been suggested that the supramamillary nucleus (SuM) could regulate ingestive and motivated behavior. López-Ferreras and colleagues found that the SuM potently contributes to ingestive and motivated behavior control, an effect contingent on sex, diet, homeostatic energy balance state, and behavior of interest.

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Hypothalamic POMC or MC4R deficiency impairs responses to hypoglycemiaPatients with diabetes are at high risk for life threatening hypoglycemia due to insulin therapy or other drugs that increase insulin secretion, because the physiological counterregulatory response to hypoglycemia is impaired in diabetes. To counteract this, it is essential to understand the physiology underlying the response to hypoglycemia. Tooke et al. show that hypothalamic Pomc as well as Mc4r are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may minimize the risk of life-threatening hypoglycemia during the treatment of diabetes.

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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.



Jaqueline Beaudry
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
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2019
Non-coding RNAs in Metabolic Diseases
Hellerup, Denmark
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