Featured Articles

Volume 7 | No. 1 | January 2018

Overexpression of nicotinamide phosphoribosyl transferase augments exercise enduranceNicotinamide adenine dinucleotide (NAD+) is an essential co-substrate for several enzyme classes. The NAD+ salvage pathway is the dominant pathway for NAD+ biosynthesis in mammals. In this pathway, nicotinamide phosphoribosyl transferase (NAMPT) plays a central role. NAMPT protein content in skeletal muscle is positively correlated with mitochondrial function, insulin sensitivity, and oxidative capacity in humans. Costford, Brouwers, et al. generated a mouse transgenic line that overexpressed NAMPT in skeletal muscle. They reveal a fascinating interaction between elevated NAMPT activity in skeletal muscle and voluntary exercise that manifests as a striking improvement of exercise endurance.

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Neurturin promotes motor neuron recruitment and neuromuscular junction formationPeroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) proteins are key regulators of mitochondrial biogenesis and energy metabolism with important roles in the biology of skeletal muscle. PGC-1α1 has been identified as a regulator of neuromuscular junction (NMJ) structure and activity. To investigate how PGC-1α isoforms affect NMJs and the role of retrograde signaling during NMJ formation, Mills, Taylor-Weiner, and colleagues used an in vitro microfluidic NMJ model. PGC-1α1 expression resulted in pre-synaptic and post-synaptic NMJ changes. Using a bioinformatics approach, the authors identified the myokine neurturin as a key component in PGC-1α1 mediated neurite recruitment to muscle.

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Macrophages sensing oxidized DAMPs reprogram their metabolism Macrophages have been shown to play essential roles in maintenance of tissue homeostasis as well as in regulation of induction and resolution of inflammation in response to tissue injury or infection. The functional plasticity of macrophages has been tied to changes in their cellular metabolism. Serbulea and colleagues show that macrophages sense danger associated molecular patterns (DAMPs) to reprogram their metabolism towards a redox-regulatory phenotype accompanied by antioxidant and inflammatory gene expression.

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Mitochondrial fission is associated with UCP1 activity Brite adipocytes, brown adipocytes that are interspersed in white adipose tissue, are promising targets for the treatment of human obesity. Compared to white adipocytes, brown and brite adipocytes possess a higher mitochondrial content and express the uncoupling protein 1 (UCP1), which facilitates a proton leak and the uncoupling of the respiratory chain. Pisani, Barquissau, et al. characterized the properties of mitochondria during the conversion of human white to brite adipocytes using the human Multipotent Adipose Derived Stem Cell (hMADS) model. They found that human brite adipocyte mitochondria had an enhanced oxidative capacity and sustained fission.

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Fatty acid oxidation is required for brown adipose tissue maintenance and thermogenic programingBrown adipose tissue (BAT) is tasked with maintaining body temperature by consuming fatty acids via nonshivering thermogenesis under cold environmental temperatures. To understand the role of fatty acid oxidation to adipose tissue structure, function, and physiology, Gonzalez-Hurtado et al. subjected mice with an adipose-specific defect in fatty acid oxidation to disparate thermogenic stimuli. They show that pharmacologic thermogenic agonists induce a loss of uncoupling protein 1 (UCP1) and BAT morphology and failed to induce UCP1 and thermogenic programing in white adipose tissue (WAT). These data show that fatty acid oxidation is critical for the maintenance of the brown adipocyte phenotype, particularly under conditions of metabolic stress.

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Vacuolar protein sorting 13C inhibits lipolysis in brown adipocytesA defining feature of brown adipocytes (BAs) is the presence of multiple small lipid droplets (LDs) that integrate triglyceride storage and mobilization. Vacuolar protein sorting 13C (VPS13C) is a protein that occurs in LDs. Ramseyer et al. find that VPS13C occupies a unique subdomain on BA LDs. Deletion of VPS13C augments basal and β-adrenergic induced lipolysis and this is likely due to increased adipose tissue triglyceride lipase trafficking to LDs. The targeting of VPS13C to a distinctive LD subdomain suggests a specialized role in the subcellular control of lipolysis and the trafficking of lipolytic products between LDs and other organelles.

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Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolismThe vagus nerve may be key to controlling glucose homeostasis by mediating the peripheral effects of insulin signaling in the central nervous system. Transcutaneous auricular vagus nerve stimulation (taVNS) can be applied to non-invasively activate the central projections of the auricular branch of the vagus nerve. Gancheva and colleagues designed a randomized, controlled, crossover clinical study in which they found that the procedure neither affects hepatic glucose metabolism nor hepatocellular lipid and ATP content in healthy humans. No differences in circulating glucoregulatory hormones and pancreatic polypeptide levels between active and sham stimulation indicate a lack of parasympathetic tone modulation with taVNS, which is confirmed by the absence of alterations in cardiac autonomic function.

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Metabolic adaptation to intermittent fasting is independent of PPARANumerous studies have shown that intermittent fasting can prevent or delay the onset of metabolic diseases. Given that fasting is characterized by the depletion of hepatic glycogen, increased lipid utilization, and elevated serum ketone bodies and that peroxisome proliferator-activated receptor alpha (PPARA) is a major regulator of fatty acid oxidation (FAO) and ketogenesis, PPARA is considered a key mediator of the fasting response. Li, Brocker, et al. placed wild-type and Ppara-null mice on an every-other-day fasting (EODF) regimen and/or treated with the potent PPARA agonist Wy-14643 to explore the effect of PPARA on the adaptive response to fasting. The results suggest that although PPARA deficiency aggravates acute fasting-induced steatosis, EODF elicits a pronounced metabolic adaptation to prevent fasting-induced hepatic steatosis independently of PPARA.

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Detection of free fatty and bile acids by ileal GLP-1 secreting cellsEnteroendocrine cells (EECs) are found scattered along the gastrointestinal tract and produce hormones that dynamically link metabolism and appetite to rates of nutrient absorption. Enteroendocrine L-cells produce several hormones, including Glucagon-like peptide-1 (GLP-1), which enhances insulin secretion and satiety. EECs detect luminal contents by G-protein coupled receptors like the G-protein coupled bile acid receptor GPBAR-1, or the free fatty acid receptor FFA1. Goldspink et al. identify the electrophysiological and second messenger responses to FFA1 and GPBAR1 activation in single L-cells using intestinal organoids from transgenic mouse models.

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CART neurons in the Arc and LHA exert differential controls on energy homeostasisThe cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide involved in the regulation of appetite control, maintenance of body weight, reward and addiction, psychostimulant effects, and neuroendocrine functions. CART is highly expressed in hypothalamic areas important for energy homeostasis regulation, including the arcuate nucleus (Arc) and lateral hypothalamic area (LHA). Lau et al. used CART-deficient mice and reintroduced CART in a neuron-specific manner. They demonstrate that CART exerts a catabolic influence in the Arc, but an anabolic influence in the LHA.

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PGC-1α functions as a co-suppressor of XBP1s to regulate glucose metabolismPeroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1 α) plays key roles in the development of obesity, insulin resistance, and type 2 diabetes. As obesity and diabetes progress, metabolically crucial organs experience elevated ER stress, which is partly due to impaired X-box binding protein 1 spliced (XBP1s) function, leading to leptin and insulin resistance. Lee and colleagues reveal a novel function of PGC-1α as a suppressor of XBP1s function, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways.

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Dual role of PTP1B in the progression and reversion of non-alcoholic steatohepatitis Protein tyrosine phosphatase 1B (PTP1B) has emerged as a major negative regulator of insulin and leptin sensitivity. The study by González-Rodríguez, Valdecantos, et al. provides an experimental model evidencing the duality of PTP1B actions in the liver. Their results strongly suggest that during non-alcoholic steatohepatitis (NASH) progression, PTP1B restrains inflammation, whereas in NASH reversion, this phosphatase targets the proliferative responses mediated by hepatocyte growth factor receptor signaling in oval liver cells. This duality of PTP1B actions must be recognized for pharmacological purposes in chronic liver diseases such as NASH.

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Why lipostatic set point systems are unlikely to evolve It is widely assumed that body fatness is regulated by a lipostatic regulatory system. By this model, a signal from the body reflecting the level of stored fat is compared to a set-point in the brain, and deviations of the body fat from the set-point result in compensatory responses. However, the molecular basis of the lipostatic set-point has never been discovered. It is thought that there are two main evolutionary drivers for a set point: having more fat will make it more likely to survive starvation, and having less fat will make it more likely to escape predators. Speakman argues that these supposed drivers are not constant in space and time, making it unlikely that a lipostatic set point evolves.

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Deficiency of leptin receptor disrupts hypothalamic circuits and causes weight increaseLeptin is an important adipokine regulating energy balance mainly through signaling in the hypothalamus. In the classic view, leptin is assumed to act mainly through leptin receptors (LepR) on hypothalamic neurons, but, more recently, the LepR has also been identified on glial cells. To investigate the significance of microglial leptin signaling, Gao, Vidal-Itriago et al. generated a mouse model with a specific LepR knockout in myeloid cells. These mice have higher body weight with hyperphagia. In the hypothalamus, pro-opiomelanocortin neuron numbers in the arcuate nucleus (ARC) and a-MSH projections from the ARC to the paraventricular nucleus (PVN) are decreased, which is accompanied by the presence of less ramified microglia with impaired phagocytic capacity in the PVN.

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Optimal housing temperatures for mice to mimic the thermal environment of humansIn metabolic research, there is an increasing understanding that environmental temperature may dramatically affect the outcome of experiments. Under normal life conditions, humans display energy expenditure values of around 1.6-1.8 times basal metabolic rate (BMR). It is evidently of utmost importance for medically related research to ensure that experimental conditions in mice resemble human conditions. Fischer and colleagues experimentally test different conditions and find that already at thermoneutrality, daily energy expenditure of mice is about 1.6 times basal metabolic rate. Thus, thermoneutral temperatures remain the preferred method of modeling human conditions for metabolic research.

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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.



Shin Jae Lee, Wolfgang Langhans
ETH Zürich, Switzerland
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