Featured Articles

Volume 21 | March 2019

GDF15 acts synergistically with liraglutide but is not necessary for bariatric surgery weight loss Growth Differentiation Factor 15 (GDF15) analogues hold great promise as pharmacological treatments for obesity as GDF15 decreases food intake. However, little is known about the biology of this system and only recently was the receptor, GDNF Family Receptor Alpha Like (GFRAL), identified. In the present study, Frikke-Schmidt et al. wanted to determine whether established anorexic treatments, specifically bariatric surgery and glucagon-like peptide 1 agonism via liraglutide, might act via the GDF15/GFRAL system. The authors found that the GDF15/GFRAL system is not critical to the effects of vertical sleeve gastrectomy or liraglutide. This indicates that future therapies targeting the GDF15/GFRAL system might complement current therapeutic options.

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FMRP controls lipid and glucose metabolism The Fragile X Mental Retardation Protein (FMRP) is an RNA-binding protein, which associates with polyribosomes to regulate mRNA translation. So far, FMRP functions and the mRNAs it targets have been explored mostly in the context of the central nervous system (CNS). Despite the wide expression of FMRP in peripheral tissues, the consequences of its absence outside the CNS are mostly unknown. Leboucher et al. demonstrate that loss of FMRP in mice markedly impacts glucose and lipid metabolism. They further show that loss of FMRP elevates hepatic protein synthesis and that FMRP likely controls the translation of key hepatic proteins involved in lipid metabolism. Finally, they provide clinical evidence that circulating metabolic markers are altered in Fragile X Syndrome patients.

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The role of C16:0 ceramide in the development of obesity and T2D: CerS6 inhibition as a novel therapeutic approachOversupply of saturated fats induces excess ceramide accumulation that leads to impaired insulin signaling and energy homeostasis, and eventually to insulin resistance and type 2 diabetes. The ceramide species C16:0 ceramide plays a key role in the development of insulin resistance. Raichur, Brunner, and colleagues investigated if the specific inhibition of ceramide synthase 6 (CerS6) might be suitable for a drug intervention approach using CerS6 antisense oligonucleotides to knock down CerS6. They report that CerS6 mediated C16:0 ceramide reduction could be an attractive target for the treatment of insulin resistance, obesity, and type 2 diabetes.

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The impact of exercise on mitochondrial dynamics and the role of Drp1 in skeletal muscleMitochondrial networks exhibit a life cycle including biogenesis, rearrangement of the network via fission-fusion, and removal of damaged or unneeded mitochondria by autophagic turnover, or mitophagy. No one study has systematically interrogated the impact of acute exercise and long-term training on all three phases of the mitochondrial life cycle. Moore et al. examined how the mitochondrial life cycle responds to three different endurance exercise interventions: acute exercise, chronic exercise training, and acute exercise after chronic exercise training. This research led to the identification of a novel role for the mitochondrial fission regulator Dynamin related protein 1 (Drp1) during acute exercise.

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Insulin action in the brain regulates mitochondrial stress responses and reduces weight gainProper control of mitochondrial function in the brain is of utter importance for normal brain function and physiology. Mitochondrial dysfunction has been observed in neurodegenerative and metabolic disorders, such as type 2 diabetes. Normally, mitochondria adapt to altered nutrient supply via the mitochondrial stress response. Wardelmann, Blümel, Rath, and colleagues found that brain insulin signaling impacts mitochondrial stress responsiveness in the hypothalamus and thus affects mitochondrial function and metabolism. Their data offer new insight into how brain insulin regulates neuronal health, acts as a neuroprotective hormone, and regulates metabolism.

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An extra copy of Down syndrome critical region 1-4 results in impaired glucose homeostasisThe prevalence of diabetes in children with Down syndrome is threefold higher than in unaffected children. Additionally, metabolic syndrome and type 2 diabetes occur at relatively early ages in those with Down syndrome. However, the molecular basis of dysregulated glucose homeostasis in patients with Down syndrome is not well understood. Seo et al. investigated the role of Down syndrome critical region 1-4 (DSCR1-4) in the liver by introducing a single extra copy of DSCR1-4 into mice. Their analysis reveals that a single extra copy of DSCR1-4 increases hepatic glucose production and expression of gluconeogenic genes, resulting in pathological states such as insulin resistance and pyruvate intolerance.

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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.



Randy J. Seeley, Henriette Frikke-Schmidt
Department of Surgery, University of Michigan, Ann Arbor, USA
Referring article

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