Featured Articles

Volume 6 | No. 5 | May 2017

Heterogeneity of hypothalamic POMC-expressing neurons The leptin-melanocortin pathway plays a key role in the control of food intake and body weight. In the hypothalamus, anorexigenic POMC neurons exist alongside orexigenic neurons that express the endogenous melanocortin antagonist agouti-related peptide (AgRP). Lam et al. report the results of single cell RNA sequencing in isolated POMC expressing neurons of the arcuate nucleus, revealing a previously unappreciated degree of heterogeneity within this population. Unexpectedly, 25% of POMC positive neurons also express high levels of AgRP. The data generated here will be of utility to better understand the fundamental nature of regulation of energy balance by the hypothalamus.

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Hypothalamic Growth Hormone Receptor Controls Hepatic Glucose Production Growth hormone (GH) signaling plays a major role in regulating body composition and glucose metabolism. Nutrient sensing, leptin receptor expressing (LepRb) neurons sense and integrate signals relevant to nutrient homeostasis to control energy balance and metabolism. Previous studies indicate that leptin can modulate GH secretion. Cady and colleagues deleted GHR specifically in LepRb neurons and examined parameters of energy homeostasis and glucose metabolism in the knockout mice. Their results identify for the first time a population of neurons responsible for the hypothalamic actions of GHR on hepatic glucose production.

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Plasma 2-Arachidonoylglycerol Is A Biomarker Of Insulin Resistance And Dyslipidemia In Lean Men And Women2-arachidonoylglycerol (2AG) is a lipid mediator of the endocannabinoid system and acts on specific cannabinoid receptors in an autocrine/paracrine fashion. Plasma concentrations and association with anthropometric and metabolic parameters reported to date do not appear to be sufficiently homogeneous for circulating 2AG to become useful for clinical purposes. Fanelli et al. investigated the relevance of 2AG as a biomarker of dysmetabolism independent of obesity. Plasma 2AG appears to be a relevant biomarker of clustering metabolic dysfunctions especially in lean men and menopausal women, thus helping in identifying subjects with elevated cardiometabolic risk despite a healthy anthropometric appearance.

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Acid sphingomyelinase deficiency protects against adipocyte hypertrophy and liver steatosisAcid sphingomyelinase (ASM) deficiency results in the lysosomal storage of sphingolipids, which disrupts a variety of signal transduction pathways and causes various cardiovascular, neurological, infectious, metabolic, and hepatic diseases. ASM inhibition has been described as a potential therapeutic agent that may reduce the progression of liver diseases. Sydor, Sowa et al. aimed to determine whether the interaction between liver tissue and adipose tissue in Asm-deficient mice protects them from diet-induced steatosis apart from other mechanisms, such as endoplasmic reticulum (ER) stress and autophagy. They show that the protective effect of ASM knockout could be associated with altered adipocyte morphology and metabolism.

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PDK1-FoxO1 pathway in AgRP neurons promotes bone formationRecently, it has been recognized that obesity causes a bone metabolism complication associated with metabolic syndrome. The 3-phosphoinositide-dependent protein kinase 1 - forkhead box O1 (PDK1-FoxO1) pathway in Agouti-related protein (AgRP) neurons regulates food consumption and energy metabolism. Sasanuma and colleagues revealed that Agrp Pdk1-/- mice exhibit short stature, shortened limbs, and decreased bone density in both cortical and cancellous bones. Their results indicate that PDK1 activity in AgRP neurons of the arcuate nucleus plays a pivotal role in regulating bone metabolism.

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GLP-1/GIP/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female micePreclinical obesity studies largely neglect female rodents because of a relative resistance to diet-induced obesity and glucose intolerance that is typically observed. A monomeric peptide with balanced agonism at the receptors for glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon has previously been shown to correct diet-induced obesity (DIO), dyslipidemia, and insulin resistance in male mice. Jall et al. demonstrate equal efficiency of the GLP-1/GIP/glucagon triagonist in reversing DIO and liver steatosis in female and male rodent models of adiposity. Their findings indicate that triagonist treatment may reduce body weight as efficiently as bariatric surgery, highlighting the potential of the monomeric triagonist as an effective treatment option for severe obesity also in women.

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Loss of hepatic DEPTOR alters the metabolic transition to fasting Mechanistic target of rapamycin complex 1 (mTORC1) is a key sensor allowing cells and tissues to adapt their metabolism in response to nutritional cues. The core proteins composing mTORC1 include a modulator of mTORC1 activity, namely DEP domain-containing mTOR-interacting protein (DEPTOR). The role of this protein in vivo is still poorly understood. Caron, Mouchiroud et al. developed a novel conditional knockout mouse for DEPTOR. They report that whole-body deletion of DEPTOR does not lead to any apparent metabolic disturbances. Postnatal liver-specific ablation of DEPTOR reduces circulating glucose upon fasting. These results indicate that DEPTOR plays an important role in liver feeding-to-fasting transition by ensuring an optimal inhibition of mTORC1 when nutrients are low.

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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.



Andrea Rozo, Doris Stoffers
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
Referring article

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Conferences & Events
September
17 − 19
2017
5th Helmholtz-Nature Medicine Diabetes Conference
Munich, Germany
October
1 − 5
2017
Lifetime Influence of Genes and Environment
Copenhagen, Denmark
October
15 − 17
2017
Cell Symposia: Metabolic Disease Therapies
San Diego, USA
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