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Volume 6 | No. 8 | August 2017

Lipid synthesis coupled to control of thermogenic programmingEarly work on adipocyte metabolism in obesity revealed that the biosynthesis of palmitate from acetyl CoA, denoted de novo lipogenesis (DNL), was markedly reduced in the insulin resistant state. Guilherme, Pedersen et al. set out to clarify the physiological role of adipocyte DNL by generating mouse models in which adipocyte fatty acid synthase (FASN) could be depleted after the animals reach maturity. Analysis of these mice following FASN deletion revealed improved glucose tolerance and showed strong inguinal white adipose tissue (iWAT) browning. Also, a markedly increased sympathetic innervation of iWAT was observed in response to induced FASN depletion in adipocytes of mature mice.

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pH changes in mitochondria during brown adipocyte activationHow mitochondrial pH is regulated in stimulated brown adipocytes, which have high metabolic capacity, is unknown. To understand the dynamic regulation of mitochondrial pH in response to adrenergic stimulation, Hou and colleagues used the pH sensitive protein mito-pHluorin. The kinetics of mitochondrial pH changes were compared with the thermogenic process. The authors show that mitochondrial pH regulation is associated with changes in mitochondrial Ca2+ levels, which are further governed by the intracellular Ca2+ store that is the endoplasmic reticulum (ER).

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Angiopoietin-like 4 directs uptake of dietary fat away from adipose during fastingAngiopoietin-like 4 (ANGPTL4), is a fasting induced inhibitor of lipoprotein lipase (LPL) and a regulator of triglyceride metabolism. In this study, Cushing and colleagues investigate the physiological mechanisms by which ANGPTL4 regulates plasma triglycerides. Their results support a model in which ANGPTL4 primarily acts locally in adipose tissue to inhibit LPL, and thus triglyceride uptake, during fasting. This inhibition would redirect triglyceride-derived fatty acids to tissues such as heart and muscle.

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Nicotinamide riboside kinases display redundancy Because of the activity of Nicotinamide adenine dinucleotide (NAD+) consuming enzymes, replenishment of NAD+ through biosynthesis and salvage pathways is vital. Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have emerged as NAD+ precursors with the potential to circumvent the adverse side effects associated with high dose niacin and augment NAD+ synthesis. Fletcher et al. have investigated NR kinase (NRK) expression in skeletal muscle and define the influence of NRKs on NR and NMN metabolism to NAD+. They show that the NRKs have overlapping and redundant activity in muscle cells critical to the conversion of exogenous NR and NMN to NAD+.

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Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonistA key regulator of islet inflammation is the pro-inflammatory cytokine interleukin-1β (IL-1β). Islet amyloid is a pathological characteristic of the pancreas in type 2 diabetes (T2D). IL-1 receptor antagonist (IL-1Ra) is a natural inhibitor of IL-1β. Hui and colleagues show that amyloid formation impairs the balance between islet IL-1β and IL-1Ra both by increasing IL-1β and reducing IL-1Ra production, thereby promoting β-cell dysfunction and death. Pharmacological strategies to reduce the IL-1β/IL-1Ra ratio may effectively protect β-cells from amyloid toxicity in conditions associated with islet amyloid formation such as T2D and human islet grafts in T1D.

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Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Thompson and colleagues demonstrate here that myeloid-specific genetic deletion of protein tyrosine phosphatase (PTP) 1B in the ApoE-/- mouse model of atherosclerosis leads to protection against atherosclerosis development, suggesting beneficial effects of PTP1B inhibition for the reduction of cardiovascular risk and treatment of CVDs.

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Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to a ketogenic diet The consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity. Douris, Desai et al. hypothesized that the sympathetic nervous system (SNS) may play a role in the adaptation to ketogenic diets. Their findings confirm that SNS activity, mediated through β-adrenergic receptors, is required for the physiologic response and adaptation to the ketogenic diet that ultimately results in weight loss.

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Nrg4 promotes fuel oxidation and a healthy adipokine profile Neuregulin 4 (Nrg4) has emerged as a brown adipose tissue (BAT) -enriched endocrine factor that exerts robust effects on hepatic lipid metabolism and systemic homeostasis. Chen and colleagues revealed a surprisingly pleiotropic effect of Nrg4 signaling on key aspects of systemic energy and glucose metabolism. They identified hepatic fatty acid oxidation and ketogenesis as a new metabolic target of endocrine signaling by Nrg4. Also, Nrg4 promotes a beneficial adipokine profile during obesity. Together, this work provides important insights into the physiological actions of Nrg4 that contribute to its beneficial effects on metabolic homeostasis.

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Repletion of branched chain amino acids reverses mTORC1 signalling but not improved metabolism Dietary protein dilution (PD), in which dietary protein intake is reduced and replaced by calories from carbohydrate and/or fat, has emerged as an influential environmental variable affecting aging and age-related disease such as type 2 diabetes (T2D). DPD can retard the development of insulin resistance and T2D in mouse models, via the induction of the liver-derived hormone fibroblast growth factor 21 (FGF21). Maida et al. show that branched chain amino acids (BCAAs) are consistently affected by dietary PD. Despite normalization of circulating BCAAs and mTORC1 signaling, they demonstrate that dietary BCAA-replacement to an AA-diluted (AAD) diet did not reverse FGF21 induction or restore hyperglycaemia in experimental T2D.

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Ghrelin-responsive mediobasal hypothalamic neurons mediate feeding responseOf all the actions mediated through ghrelin receptors (GHSRs), one of the most robust and well-characterized is the induction of an acute feeding response after peripheral or central administration of ghrelin. Mani et al. tested whether the activity of mediobasal hypothalamic (MBH) GHSR neurons is required for the normal rebound food intake following fasting. Their results suggest that the activity of MBH GHSR neurons is required for the full acute orexigenic response to administered ghrelin and the usual rebound food intake response following a 24 hour fast and is sufficient to induce spontaneous food intake.

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Dietary sugars, not lipids, drive hypothalamic inflammationThe hypothalamus of hypercalorically diet-induced obese animals is characterized by an increased inflammatory response. In hypercaloric diet-induced obesity, dietary fats, and especially saturated fatty acids, are considered to be the essential component initiating pro-inflammatory responses in the hypothalamus. Gao, Bielohuby et al. documented that the mediobasal hypothalamic inflammatory response occurs in response to high-fat diets rich in carbohydrates (high-carbohydrate high-fat (HCHF) diets) but not in response to a low-carbohydrate, high-fat (LCHF) diet.

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Serotonergic modulation of the activity of GLP-1-producing neurons Glucagon-like peptide-1 (GLP-1) is an incretin best known for its role in glucose homeostasis and appetite regulation. Within the brain, GLP-1 is produced by preproglucagon (PPG) neurons in the lower brainstem. Serotonin (5-hydroxytryptamine; 5-HT) is another key neurotransmitter involved in both regulation of stress and anxiety and control of food intake. Holt and colleagues have investigated the cellular effects of 5-HT on PPG neurons, as well as the innervation that underlies these effects. Their data suggest a multifaceted link between 5-HT and central GLP- 1, which is tightly regulated through excitatory or inhibitory responses to 5-HT occurring within different subcellular compartments of PPG neurons.

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Maternal obesity programs increased leptin gene expression in offspringAccording to the Developmental Origin of Health and Disease (DOHaD) concept [1], maternal obesity and accelerated growth in neonates predispose offspring to obesity and metabolic pathologies. Adult rat offspring from high-fat diet-fed dams (HF) exhibits hypertrophic adipocyte, hyperleptinemia, and increased leptin mRNA levels in a depot-specific manner. Lecoutre et al. show that maternal obesity differently affects epigenetic remodeling of a promoter and two enhancers linked to higher leptin gene expression during visceral perirenal and subcutaneous inguinal deposits development in HF neonates. They also report that retained active marks that are correlated with persistent increased leptin mRNA levels occur in a depot-specific manner in adult obesity-prone HF offspring.

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A Unique Resource for Studying Organ Crosstalk in DiabetesTo generate a unique resource for studying consequences of chronic insulin insufficiency and hyperglycemia in a multi-tissue, multi-omics approach, Blutke et al. generated a complex biobank of more than 50 different tissues and body fluids from two-year-old MIDY pigs and WT littermate controls. A comprehensive standardized protocol was established to ensure uniform high quality of representative samples for a broad spectrum of analyses, including molecular profiling as well as qualitative and quantitative morphological investigations. To characterize the quality of samples in the Munich MIDY pig biobank, the authors extracted and characterized RNA and proteins from a subset of tissues. These pilot studies revealed excellent sample quality. Future detailed omics studies will provide insights into tissue specific molecular changes induced by chronic hyperglycemia and insulin insufficiency.

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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.



Ursula Neumann
University of British Columbia, Vancouver, Canada
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