Featured Articles

Volume 5 | No. 8 | August 2016

An ancestral role for the mitochondrial pyruvate carrierMitochondrial pyruvate import is mediated by two proteins, the Mitochondrial Pyruvate Carrier 1 and 2 (MPC1 and MPC2), which form a hetero-oligomeric complex in the inner mitochondrial membrane. McCommis, Hodges, Bricker et al. demonstrate that the MPC plays a central role in glucose-stimulated insulin secretion (GSIS) and systemic glucose homeostasis. MPC deficiency in Drosophila or the β-cells of mice leads to elevated blood glucose concentrations, glucose intolerance, and reduced GSIS. Pancreas-specific MPC deficiency results in impaired islet glucose metabolism and KATP channel hyperactivity. The authors show that glucose increases MPC activity in cultured INS-1 cells in a concentration-dependent manner, suggesting that glucose sensing is coupled to mitochondrial pyruvate transport and utilization to support efficient GSIS.

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miR-125b affects mitochondrial biogenesis and impairs brite adipocyte formationBrown adipose tissue (BAT) dissipates energy in the form of heat by uncoupling the mitochondrial respiratory chain from ATP synthesis. Also, white adipose tissue contains thermogenic fat cells called “brown-inwhite” (“brite”), and “beige” or inducible brown adipocytes. Giroud and colleagues analyze the role of miR-125b-5p in the browning/britening of white adipocytes in human and murine cell models and tissues. The authors show that miR-125b-5p plays an important role in the modulation of brite and brown adipocyte function by targeting mitochondriogenesis and oxygen consumption.

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Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesisAdipose tissue is connected to the central nervous system via afferent and efferent nerve fibers directly innervating each fat depot. Garretson and colleagues investigate if white adipose tissue (WAT) lipolysis and/or its products are sufficient to drive spinal afferent nerves receiving sensory input from subcutaneous inguinal WAT. Their findings illustrate a functional neural connectivity between WAT and brown adipose tissue (BAT) that acutely induces BAT thermogenesis.

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Demonstration of a day-night rhythm in human skeletal muscle oxidative capacityMany metabolic processes are synchronized to day-night cycles by the circadian clock, thereby anticipating changes in metabolic activity associated with feeding or fasting and physical activity or rest. Van Moorsel, Hansen et al. demonstrate the presence of a profound day-night rhythm in human skeletal muscle mitochondrial oxidative capacity. Peak oxidative capacity and highest resting energy expenditure coincide at the end of the day, partly matching the time phase of peak physical performance as described in the literature. In addition, the authors found significant variations over time in proteins involved in mitochondrial dynamics, possibly linking the circadian clock with mitochondrial metabolism.

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mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that is found in two distinct mTOR complexes, mTOR complex 1 and mTOR complex 2 (mTORC2). Kleinert and colleagues characterize new aspects of mTORC2 and AMPK biology in muscle lipid metabolism by showing that mTORC2 and AMPK are negative and positive regulators of lipid storage, respectively, via Perilipin 3. In addition, lack of mTORC2 activity in muscle causes a greater reliance on fat as an energy substrate and repartitioning of lean to fat mass.

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The F-actin modifier villin regulates insulin granule dynamics and exocytosisThe islet cell autoantigen 512 (Ica512) tethers insulin secretory granules (SGs) to actin microfilaments. Mziaut and colleagues analyze the gene expression profile of Ica512-depleted mouse islets. They show that Ica512 depletion leads to downregulation of the F-actin modifier villin in β cells, increasing the size of actin cages surrounding cortical SGs and thus their motility and exocytosis in basal conditions while reducing glucose-stimulated insulin release. The data indicate that villin is key for tight control of insulin SG mobility and exocytosis.

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Leptin and insulin engage specific PI3K subunits in hypothalamic SF1 neuronsSteroidogenic factor 1 (SF1)-expressing neurons within the ventromedial nucleus of hypothalamus (VMH SF1 neurons) regulate energy balance and glucose homeostasis. Sohn and colleagues characterize the acute effects of leptin and insulin on VMH SF1 neurons and identify the role of specific phosphatidylinositol-3-kinase (PI3K) catalytic subunit isoforms (p110a and p110b) in this response. They provide further evidence that SF1 neurons are heterogeneous in their acute response to leptin and insulin and demonstrate specificity in receptor-enzyme-target ion channel.

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Sexually dimorphic brain fatty acid composition in low and high fat diet-fed miceRodriguez-Navas and colleagues demonstrate that male and female brains of mice differ in their fatty acid composition even when fed a regular/chow diet. Additionally, when chronically exposed to a Western-style high fat diet, this sexual dimorphism continues to exist. Males have an increased percentage of saturated fatty acids and reductions in ω6-polyunsaturated fatty acids (ω6-PUFAs) when compared to females. The findings of the authors suggest that ω6-PUFA linoleic acid, which is higher in female brains, has an anti-inflammatory role and reduces palmitic acid-induced inflammation.

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Fibroblast growth factor 21 has no direct role in regulating fertility in female miceFibroblast growth factor 21 (FGF21) has been proposed as a regulator of fertility in rodents based on the finding that female mice overexpressing FGF21 to supraphysiologic levels (FGF21-Tg) have delayed onset of puberty and remain infertile through adulthood. Singhal et al. confirm that FGF21-Tg mice consuming a chow diet are indeed infertile. In contrast to this finding, the authors observe that female mice consuming a ketogenic diet (KD), a model with dramatic increases in hepatic synthesis of FGF21 and elevated serum levels, demonstrate normal estrus cycles and remain fertile. Further, infusion of FGF21 into the lateral ventricle has no effect on fertility in wild type (WT) female mice. Mice lacking FGF21 (FGF21-KO) have the same response as WT animals to the fasting induced suppression of cycling. High fat diet feeding to FGF21-Tg mice restores fertility. Together, these results render unlikely the claim that FGF21 has a physiologically relevant influence on fertility in female mice via action on the gonadotropic axis.

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Male-lineage transmission of an acquired metabolic phenotypeOffspring phenotypes can be affected by parental health or parental environmental exposures, independent of variation in the inherited DNA sequence. Cropley, Eaton et al. demonstrate transgenerational inheritance of an acquired metabolic trait in mammals. The data of the authors implicate small RNAs in the mechanism of inheritance. If the phenomenon observed here translates to humans, the findings suggest that individuals with obese paternal ancestry could avoid the deleterious effects of metabolic programming with dietary intervention, yet still propagate the propensity for metabolic dysfunction to their offspring.

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Optogenetic activation of leptin- and glucose-regulated GABAergic neurons in dorsomedial hypothalamus promotes food intakeThe dorsomedial hypothalamus (DMH) is considered an orexigenic nucleus as a lesion to the DMH reduces food intake and body weight and induces resistance against diet-induced obesity. Otgon-Uul, Suyama et al. show that DMH GABAergic neurons are hyperpolarized by leptin and depolarized by lowering glucose. Further, the optogenetic activation of DMH GABAergic neurons elicits inhibitory synaptic transmission to the paraventricular nucleus of hypothalamus (PVN), where anorexigenic neurons are localized, and promotes food intake.

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The role of autonomic efferents and uncoupling protein 1 in the glucose-lowering effect of leptin therapyLeptin can reverse hyperglycemia in rodent models of type 1 diabetes, independent of food intake and without raising circulating insulin levels. Denroche and colleagues report that neither subdiaphragmatic vagotomy nor partial chemical sympathectomy attenuates the glucose-lowering action of leptin. In addition, the authors demonstrate that although leptin induces Ucp1 expression and thermogenesis in BAT of STZ-diabetic mice, diabetic Ucp1 knockout mice are not refractory to leptin therapy.

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Microbially produced glucagon-like peptide 1 improves glucose tolerance in miceGlucagon-like peptide 1 (GLP-1) is released from enteroendocrine L-cells after food intake. It stimulates insulin release, reduces appetite, and slows down gastric emptying. Arora and colleagues demonstrate the efficacy of a Lactococcus lactis strain that is genetically modified to produce GLP-1, stimulating insulin secretion in isolated mouse islets and improving glucose tolerance in mice fed either chow or a high-fat diet (HFD). In summary, these findings provide evidence that recombinant L. lactis strains may have potential clinical applications.

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Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketonesGlucagon suppression can reverse or prevent type 1 diabetes in rodents suggesting that dysregulated glucagon is also required for development of diabetic symptoms. Neumann and colleagues show that the absence of glucagon signalling modestly improves diabetic symptoms in insulin knockout mice, but this improvement is insufficient to promote survival. The authors provide unequivocal evidence that it is not possible to protect from the catabolic consequences due to the complete loss of insulin by eliminating glucagon action.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

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Jennifer Lee
University of Toronto, Canada
Referring article

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