Spathaspora marinasilvae sp. nov., a xylose-fermenting yeast isolated from galleries of passalid beetles and rotting wood in the Amazonian rainforest biome.

Four yeast isolates were obtained from rotting wood and galleries of passalid beetles collected in different sites of the Brazilian Amazonian Rainforest in Brazil. This yeast produces unconjugated allantoid asci each with a single elongated ascospore with curved ends. Sequence analysis of the internal transcribed spacer-5.8 S region and the D1/D2 domains of the large subunit ribosomal RNA (rRNA) gene showed that the isolates represent a novel species of the genus Spathaspora. The novel species is phylogenetically related to a subclade containing Spathaspora arborariae and Spathaspora suhii. Phylogenomic analysis based on 1884 single-copy orthologs for a set of Spathaspora species whose whole genome sequences are available confirmed that the novel species represented by strain UFMG-CM-Y285 is phylogenetically close to Sp. arborariae. The name Spathaspora marinasilvae sp. nov. is proposed to accommodate the novel species. The holotype of Sp. marinasilvae is CBS 13467 T (MycoBank 852799). The novel species was able to accumulate xylitol and produce ethanol from d-xylose, a trait of biotechnological interest common to several species of the genus Spathaspora.

Spencermartinsiella nicolii sp. nov., a potential opportunistic pathogenic yeast species isolated from rotting wood in Brazil.

Nineteen isolates representing a candidate for a novel yeast species belonging to the genus Spencermartinsiella were recovered from rotting wood samples collected at different sites in Atlantic Rainforest and Amazonian Forest ecosystems in Brazil. Similarity search of the nucleotide sequence of the intergenic spacer (ITS)-5.8S and large subunit D1/D2 regions of the ribosomal gene cluster showed that this novel yeast is closely related to Spencermartinsiella cellulosicola. The isolates differ by four nucleotide substitutions in the D1/D2 domain and six substitutions and 31 indels in the ITS region from the holotype of S. cellulosicola. Phylogenomic analysis based on 1474 single-copy orthologues for a set of Spencermartinsiella species whose whole genome sequences are available confirmed that the novel species is phylogenetically close to S. cellulosicola. The low average nucleotide identity value of 83% observed between S. cellulosicola and the candidate species confirms that they are distinct. The novel species produced asci with hemispherical ascospores. The name Spencermartinsiella nicolii sp. nov. is proposed. The holotype is CBS 14238T. The MycoBank number is MB855027. Interestingly, the D1/D2 sequence of the S. nicolii was identical to that of an uncultured strain of Spencermartinsiella causing systemic infection in a male adult crocodile (Crocodylus niloticus). The characterization of some virulence factors and antifungal susceptibility of S. nicolii isolates suggest that this yeast may be an opportunistic pathogen for animals, including humans; the isolates grow at 37 °C.

Distinct signaling by insulin and IGF-1 receptors and their extra- and intracellular domains.

Insulin and insulin-like growth factor 1 (IGF-1) receptors share many downstream signaling pathways but have unique biological effects. To define the molecular signals contributing to these distinct activities, we performed global phosphoproteomics on cells expressing either insulin receptor (IR), IGF-1 receptor (IGF1R), or chimeric IR-IGF1R receptors. We show that IR preferentially stimulates phosphorylations associated with mammalian target of rapamycin complex 1 (mTORC1) and Akt pathways, whereas IGF1R preferentially stimulates phosphorylations on proteins associated with the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases), and cell cycle progression. There were also major differences in the phosphoproteome between cells expressing IR versus IGF1R in the unstimulated state, including phosphorylation of proteins involved in membrane trafficking, chromatin remodeling, and cell cycle. In cells expressing chimeric IR-IGF1R receptors, these differences in signaling could be mapped to contributions of both the extra- and intracellular domains of these receptors. Thus, despite their high homology, IR and IGF1R preferentially regulate distinct networks of phosphorylation in both the basal and stimulated states, allowing for the unique effects of these hormones on organismal function.

Saccharomycopsis praedatoria sp. nov., a predacious yeast isolated from soil and rotten wood in an Amazonian rainforest biome.

Three yeast isolates were obtained from soil and rotting wood samples collected in an Amazonian rainforest biome in Brazil. Comparison of the intergenic spacer 5.8S region and the D1/D2 domains of the large subunit rRNA gene showed that the isolates represent a novel species of the genus Saccharomycopsis. A tree inferred from the D1/D2 sequences placed the novel species near a subclade containing Saccharomycopsis lassenensis, Saccharomycopsis fermentans, Saccharomycopsis javanensis, Saccharomycopsis babjevae, Saccharomycopsis schoenii and Saccharomycopsis oosterbeekiorum, but with low bootstrap support. In terms of sequence divergence, the novel species had the highest identity in the D1/D2 domains with Saccharomycopsis capsularis, from which it differed by 36 substitutions. In contrast, a phylogenomic analysis based on 1061 single-copy orthologs for a smaller set of Saccharomycopsis species whose whole genome sequences are available indicated that the novel species represented by strain UFMG-CM-Y6991 is phylogenetically closer to Saccharomycopsis fodiens and Saccharomycopsis sp. TF2021a (=Saccharomycopsis phalluae). The novel yeast is homothallic and produces asci with one spheroidal ascospore with an equatorial or subequatorial ledge. The name Saccharomycopsis praedatoria sp. nov. is proposed to accommodate the novel species. The holotype of Saccharomycopsis praedatoria is CBS 16589T. The MycoBank number is MB849369. S. praedatoria was able to kill cells of Saccharomyces cerevisiae by means of penetration with infection pegs, a trait common to most species of Saccharomycopsis.

Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver.

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show that Arrdc3 is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction in Arrdc3 messenger RNA, while, conversely, mice with liver-specific KO of Arrdc3 (L-Arrdc3 KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus, Arrdc3 is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

Dietary Protein Modulates the Efficacy of Taurine Supplementation on Adaptive Islet Function and Morphology in Obesity.

Adaptation of islet ß-cell mass and function under limiting or excess nutrient availability is critical for maintenance of glucose homeostasis. Taurine regulates islet function of obese mice in normal and low dietary protein conditions, but whether this involves remodeling of the endocrine pancreas architecture is not well understood. Here, we carried functional and morphometric evaluation of the endocrine pancreas of normal and protein-restricted mice fed a high-fat diet (HFD) and investigated the role of taurine supplementation. Weaned mice were placed in a normal (C) or a low-protein diet (R) for 6 weeks, followed by HFD for 8 weeks (CH and RH). Half of HFD groups received 5% taurine supplementation since weaning (CHT and RHT) until the end of the experiment. Isolated islets from both CH and RH groups showed increased insulin release in association with increased pancreas weight and independently of changes in islet or ß-cell area. In normal protein CHT mice, taurine supplementation prevented obesity-induced insulin hypersecretion and promoted increased islet and ß-cell areas in association with increased protein expression of the proliferation marker, PCNA. On a low-protein background, taurine effects on islet function and morphology were blunted, but it prevented obesity-induced DNA fragmentation. In summary, taurine regulates islet function and morphology to improve the adaptive response to diet-induced obesity, but these effects are dependent on adequate dietary protein levels.

Defining the underlying defect in insulin action in type 2 diabetes.

Insulin resistance is one of the earliest defects in the pathogenesis of type 2 diabetes. Over the past 50 years, elucidation of the insulin signalling network has provided important mechanistic insights into the abnormalities of glucose, lipid and protein metabolism that underlie insulin resistance. In classical target tissues (liver, muscle and adipose tissue), insulin binding to its receptor initiates a broad signalling cascade mediated by changes in phosphorylation, gene expression and vesicular trafficking that result in increased nutrient utilisation and storage, and suppression of catabolic processes. Insulin receptors are also expressed in non-classical targets, such as the brain and endothelial cells, where it helps regulate appetite, energy expenditure, reproductive hormones, mood/behaviour and vascular function. Recent progress in cell biology and unbiased molecular profiling by mass spectrometry and DNA/RNA-sequencing has provided a unique opportunity to dissect the determinants of insulin resistance in type 2 diabetes and the metabolic syndrome; best studied are extrinsic factors, such as circulating lipids, amino acids and other metabolites and exosomal microRNAs. More challenging has been defining the cell-intrinsic factors programmed by genetics and epigenetics that underlie insulin resistance. In this regard, studies using human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway. Understanding how these multi-layered molecular networks modulate insulin action and metabolism in different tissues will open new avenues for therapy and prevention of type 2 diabetes and its associated pathologies.

Yeast communities associated with cacti in Brazil and the description of Kluyveromyces starmeri sp. nov. based on phylogenomic analyses.

Yeast communities associated with cacti were studied in three ecosystems of Southeast, Central and North Brazil. A total of 473 yeast strains belonging to 72 species were isolated from 190 samples collected. Cactophilic yeast species were prevalent in necrotic tissues, flowers, fruits and insects of cacti collected in Southeast and North Brazil. Pichia cactophila, Candida sonorensis and species of the Sporopachydermia complex were the most prevalent cactophilic species in Southeast and Central regions. Kodamaea nitidulidarum, Candida restingae and Wickerhamiella cacticola were frequently associated with cactus flowers and fruits. The diversity of yeasts associated with the substrates studied was high. Twenty-one novel species were found. One is described here as Kluyveromyces starmeri sp. nov. based on 21 isolates obtained from necrotic tissues, flowers, fruits and associated insects of the columnar cacti Cereus saddianus, Micranthocereus dolichospermaticus and Pilosocereus arrabidae in two different ecosystems in Brazil. Phylogenetic analyses of sequences encoding the gene of the small subunit (SSU) rRNA gene, the internal transcribed spacer, the 5.8S rRNA gene and the D1/D2 domains of the large subunit (LSU) rRNA showed that the species is related to Kluyveromyces dobzhanskii, Kluyveromyces lactis and Kluyveromyces marxianus. Phylogenomic analyses based on 1264 conserved genes shared among the new species and 19 other members of the Saccharomycetaceae confirmed this phylogenetic relationship. The holotype is K. starmeri sp. nov. CBS 16103T (=UFMG-CM-Y3682T ). The Mycobank number is MB 836817.

Reduced glucose-induced insulin secretion in low-protein-fed rats is associated with altered pancreatic islets redox status.

In the present study, we investigated the relationship between early life protein malnutrition-induced redox imbalance, and reduced glucose-stimulated insulin secretion. After weaning, male Wistar rats were submitted to a normal-protein-diet (17%-protein, NP) or to a low-protein-diet (6%-protein, LP) for 60 days. Pancreatic islets were isolated and hydrogen peroxide (H2 O2 ), oxidized (GSSG) and reduced (GSH) glutathione content, CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and catalase (CAT) gene expression, as well as enzymatic antioxidant activities were quantified. Islets that were pre-incubated with H2 O2 and/or N-acetylcysteine, were subsequently incubated with glucose for insulin secretion measurement. Protein malnutrition increased CAT mRNA content by 100%. LP group SOD1 and CAT activities were 50% increased and reduced, respectively. H2 O2 production was more than 50% increased whereas GSH/GSSG ratio was near 60% lower in LP group. Insulin secretion was, in most conditions, approximately 50% lower in LP rat islets. When islets were pre-incubated with H2 O2 (100 µM), and incubated with glucose (33 mM), LP rats showed significant decrease of insulin secretion. This effect was attenuated when LP islets were exposed to N-acetylcysteine.

Regulation of glucose and lipid metabolism by the pancreatic and extra-pancreatic actions of taurine.

The beneficial actions of L-taurine (Tau) against glucose intolerance, obesity, type 2 diabetes (T2D), and non-alcoholic fat liver disease (NAFLD) have been linked to its antioxidant and anti-inflammatory effects, which ameliorate tissue insulin sensitivity. Importantly, there are several lines of evidence that indicate a direct action of Tau on the endocrine pancreas to regulate the secretion and paracrine actions of insulin, glucagon, and somatostatin. Furthermore, Tau can also ameliorate glucose metabolism through the enhancement of insulin signaling. However, some of the benefits of Tau upon intermediary metabolism may manifest via considerable antagonism of the action of insulin. Therefore, this review discusses the mechanisms of action by which Tau may regulate endocrine pancreatic morphofunction, and glucose and lipid homeostasis.

Diet-induced glucose homeostasis dysregulation is enhanced by taurine supplementation in ovariectomized mice.

Low levels of estrogens are associated with obesity-related comorbidities. Mice with lower levels of estrogens are thereby more sensitive to the effects of a high-fat-diet (HFD) for the development of glucose intolerance and insulin resistance. Studies in vivo have demonstrated that taurine (TAU) supplementation prevents glucose and insulin resistance. Thus, we aimed to investigate the potential beneficial effects of TAU supplementation on glucose homeostasis of mice with low levels of estrogens fed with a HFD. 3-month-old female C57BL/6J mice underwent bilateral ovariectomy (OVX). After 1 week of recovery, mice were divided into 4 groups and either received: a standard chow diet (OVXC), chow diet plus drinking water enriched with 3% of TAU (OVXCT), HFD (OVXH), and HFD plus supplementation of TAU (OVXHT) for 14 weeks. Exposure to the HFD increased adiposity and plasma levels of glucose and insulin. Contrary to our prediction, the addition of TAU enhanced the deleterious effects of the HFD. Glucose and insulin tolerance tests (ipGTT and ipITT) indicated that mice maintained on the HFD + TAU had worse glucose intolerance and insulin resistance that was linked to lower insulin signaling in skeletal muscle and liver. Insulin secretion of isolated pancreatic islets of OVXH mice was higher than OVXC, and the addition of TAU associated with a HFD did not modulate insulin secretion, suggesting a failure of pancreatic ß cells of OVXHT mice. These results suggest that despite the beneficial reports of TAU, it should be used cautiously in situations where the levels of estrogens are low.

Scheffersomyces stambukii f.a., sp. nov., a d-xylose-fermenting species isolated from rotting wood.

Two isolates representing a new species of Scheffersomyces were isolated from rotting wood samples collected in an Amazonian forest ecosystem in Brazil. Analysis of the sequences of the D1/D2 domains showed that this new species is phylogenetically related to Scheffersomyces NYMU 15730, a species without a formal description, and the two are in an early emerging position with respect to the xylose-fermenting subclade containing Scheffersomyces titanus and Scheffersomyces stipitis. Phylogenomic analyses using 474 orthologous genes placed the new species in an intermediary position between Scheffersomyces species and the larger genus Spathaspora and the Candida albicans/Lodderomyces clade. The novel species, Scheffersomyces stambukii f.a., sp. nov., is proposed to accommodate these isolates. The type strain of Scheffersomyces stambukii sp. nov. is UFMG-CM-Y427T (=CBS 14217T). The MycoBank number is MB 824093. In addition, we studied the xylose metabolism of this new species.

Spathaspora boniae sp. nov., a D-xylose-fermenting species in the Candida albicans/Lodderomyces clade.

Two yeast isolates producing asci-containing elongate ascospores with curved ends typical of the genus Spathaspora were isolated from rotting wood samples collected in an Atlantic rainforest ecosystem in Brazil. Phylogenetic analysis of the LSU rRNA gene D1/D2 domain sequences demonstrated that the strains represent a new species and placed it next to Candida blackwellae, in a clade that also contains Candida albicans and Candida dubliniensis. Other sequences of the ribosomal gene cluster supported same placementin the same clade, and a phylogenomic analysis placed this new species in an early emerging position relative to the larger C. albicans/Lodderomyces clade. One interpretation is that the genus Spathaspora is, in fact, paraphyletic. In conformity with this view, we propose the novel species Spathaspora boniae sp. nov. to accommodate the isolates. The type strain of Spathaspora boniae sp. nov. is UFMG-CM-Y306T (=CBS 13262T). The MycoBank number is MB 821297. A detailed analysis of xylose metabolism was conducted for the new species.

Benefits of L-alanine or L-arginine supplementation against adiposity and glucose intolerance in monosodium glutamate-induced obesity.

PURPOSE: L-alanine (Ala) and L-arginine (Arg) have been reported to regulate pancreatic ß-cell physiology and to prevent body fat accumulation in diet-induced obesity. Here, we assessed growth and adiposity parameters, glucose tolerance, insulin secretion and the expression of insulin and nutrient-regulated proteins in monosodium glutamate (MSG)-obese mice supplemented with either Ala or Arg. METHODS: Male newborn C57Bl/6 mice received a daily subcutaneous injection of MSG or saline solution (CTL group), during the first 6 days of life. From 30 to 90 days of age, MSG and CTL mice received or not 2.55 % Ala (CAla or MArg groups) or 1.51 % Arg-HCl (CArg or MArg groups) in their drinking water. RESULTS: Adult MSG mice displayed higher adiposity associated with lower phosphorylation of the adipogenic enzyme, ACC, in adipose tissue. Glucose intolerance in MSG mice was linked to lower insulin secretion and to lower expression of IRß in adipose tissue, as well as AS160 phosphorylation in skeletal muscle. Perigonadal fat depots were smaller in Ala and Arg mice, while retroperitoneal fat pads were decreased by Ala supplementation only. Both Ala and Arg improved fed-state glycemia as well as IRß and pAS160 content, but only Ala led to improved glucose tolerance and insulin secretion. Adipostatic signals were increased in MAla mice, as indicated by enhanced AMPK phosphorylation and pACC content in fat depots. CONCLUSIONS: Ala supplementation led to more pronounced metabolic improvements compared to Arg, possibly due to suppression of lipogenesis through activation of the AMPK/ACC pathway.

Taurine supplementation preserves hypothalamic leptin action in normal and protein-restricted mice fed on a high-fat diet.

Malnutrition programs the neuroendocrine axis by disruption of food-intake control, leading to obesity. Taurine (Tau) is neuroprotective and improves anorexigenic actions in the hypothalamus. We evaluated the hypothalamic gene-expression profile and food-intake control in protein-restricted mice submitted to a high-fat diet (HFD) and Tau supplementation. Mice were fed on a control (14 % protein-C) or a protein-restricted diet (6 % protein-R) for 6 weeks. Thereafter, mice received, or not, HFD for 8 weeks (CH and RH) with or without 5 % Tau supplementation (CHT and RHT). Protein restriction led to higher food intake, but calories were matched to controls. Excessive calorie intake occurred in HFD mice and this was prevented by Tau supplementation only in the CH group. Additionally, RH and CH mice developed hypothalamic leptin resistance, which was prevented by Tau. Global alterations in the expressions of genes involved in hypothalamic metabolism, cellular defense, apoptosis and endoplasmic reticulum stress pathways were induced by dietary manipulations and Tau treatment. The orexigenic peptides NPY and AgRP were increased by protein restriction and lowered by the HFD. The anorexigenic peptide Pomc was increased by HFD, and this was prevented by Tau only in CH mice. Thus, food intake was disrupted by dietary protein restriction and obesity. HFD-induced alterations were not enhanced by previous protein deficiency, but the some beneficial effects of Tau supplementation upon food intake were blunted by protein restriction. Tau effects upon feeding behavior control are complex and involve interactions with a vast gene network, preventing hypothalamic leptin resistance.

Hydrogen peroxide production regulates the mitochondrial function in insulin resistant muscle cells: effect of catalase overexpression.

The mitochondrial redox state plays a central role in the link between mitochondrial overloading and insulin resistance. However, the mechanism by which the ROS induce insulin resistance in skeletal muscle cells is not completely understood. We examined the association between mitochondrial function and H2O2 production in insulin resistant cells. Our hypothesis is that the low mitochondrial oxygen consumption leads to elevated ROS production by a mechanism associated with reduced PGC1α transcription and low content of phosphorylated CREB. The cells were transfected with either the encoded sequence for catalase overexpression or the specific siRNA for catalase inhibition. After transfection, myotubes were incubated with palmitic acid (500µM) and the insulin response, as well as mitochondrial function and fatty acid metabolism, was determined. The low mitochondrial oxygen consumption led to elevated ROS production by a mechanism associated with ß-oxidation of fatty acids. Rotenone was observed to reduce the ratio of ROS production. The elevated H2O2 production markedly decreased the PGC1α transcription, an effect that was accompanied by a reduced phosphorylation of Akt and CREB. The catalase transfection prevented the reduction in the phosphorylated level of Akt and upregulated the levels of phosphorylated CREB. The mitochondrial function was elevated and H2O2 production reduced, thus increasing the insulin sensitivity. The catalase overexpression improved mitochondrial respiration protecting the cells from fatty acid-induced, insulin resistance. This effect indicates that control of hydrogen peroxide production regulates the mitochondrial respiration preventing the insulin resistance in skeletal muscle cells by a mechanism associated with CREB phosphorylation and ß-oxidation of fatty acids.

Taurine supplementation increases K(ATP) channel protein content, improving Ca2+ handling and insulin secretion in islets from malnourished mice fed on a high-fat diet.

Pancreatic ß-cells are highly sensitive to suboptimal or excess nutrients, as occurs in protein-malnutrition and obesity. Taurine (Tau) improves insulin secretion in response to nutrients and depolarizing agents. Here, we assessed the expression and function of Cav and KATP channels in islets from malnourished mice fed on a high-fat diet (HFD) and supplemented with Tau. Weaned mice received a normal (C) or a low-protein diet (R) for 6 weeks. Half of each group were fed a HFD for 8 weeks without (CH, RH) or with 5% Tau since weaning (CHT, RHT). Isolated islets from R mice showed lower insulin release with glucose and depolarizing stimuli. In CH islets, insulin secretion was increased and this was associated with enhanced KATP inhibition and Cav activity. RH islets secreted less insulin at high K(+) concentration and showed enhanced KATP activity. Tau supplementation normalized K(+)-induced secretion and enhanced glucose-induced Ca(2+) influx in RHT islets. R islets presented lower Ca(2+) influx in response to tolbutamide, and higher protein content and activity of the Kir6.2 subunit of the KATP. Tau increased the protein content of the α1.2 subunit of the Cav channels and the SNARE proteins SNAP-25 and Synt-1 in CHT islets, whereas in RHT, Kir6.2 and Synt-1 proteins were increased. In conclusion, impaired islet function in R islets is related to higher content and activity of the KATP channels. Tau treatment enhanced RHT islet secretory capacity by improving the protein expression and inhibition of the KATP channels and enhancing Synt-1 islet content.

Effects of taurine supplementation upon food intake and central insulin signaling in malnourished mice fed on a high-fat diet.

Feeding behavior is a major determinant of body composition, adiposity, and glucose homeostasis. Both obesity and malnutrition are risk factors for the metabolic syndrome and are associated with altered food intake. Here we assessed the effects of taurine (TAU) supplementation upon adiposity, food intake, and central insulin signaling in malnourished mice fed on a high-fat diet (HFD). Weaned male C57BL/6 mice were fed a control (14% protein-C) or a protein-restricted (6% protein-R) diet. After 6 weeks, both groups received or not HFD for 8 weeks (CH and RH). Half of the HFD groups were supplemented with 5% TAU (CHT and RHT). Both HFD groups were overweight and showed increased perigonadal and retroperitoneal fat pads. TAU supplementation attenuated obesity in CHT but not in RHT mice. HFD induced hypercholesterolemia and glucose intolerance, although only CH group presented fasting hyperglycemia. TAU supplementation also improved glucose homeostasis only in CHT mice. Western blot analysis showed a reduction of 55% in CH hypothalamic content of phosphorylated IRS-1 (pIRS-1) at basal condition compared with C. TAU treatment increased 35% Akt phosphorylation levels in CHT without modification in RHT hypothalamus. However, TAU supplementation did not alter hypothalamic pIRS-1 amount. CH and RH mice presented increased calorie intake that was normalized in CHT but not in RHT. In conclusion, mice fed on an HFD developed obesity, hypercholesterolemia, glucose intolerance, and increased calorie intake. TAU promoted increased hypothalamic insulin action only in CH mice which was linked to prevention of overfeeding, obesity, and glucose intolerance. Protein-restriction promoted metabolic damages that were not prevented by TAU supplementation.

Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis.

Insulin acts through the insulin receptor (IR) tyrosine kinase to exert its classical metabolic and mitogenic actions. Here, using receptors with either short or long deletion of the ß-subunit or mutation of the kinase active site (K1030R), we have uncovered a second, previously unrecognized IR signaling pathway that is intracellular domain-dependent, but ligand and tyrosine kinase-independent (LYK-I). These LYK-I actions of the IR are linked to changes in phosphorylation of a network of proteins involved in the regulation of extracellular matrix organization, cell cycle, ATM signaling and cellular senescence; and result in upregulation of expression of multiple extracellular matrix-related genes and proteins, down-regulation of immune/interferon-related genes and proteins, and increased sensitivity to apoptosis. Thus, in addition to classical ligand and tyrosine kinase-dependent (LYK-D) signaling, the IR regulates a second, ligand and tyrosine kinase-independent (LYK-I) pathway, which regulates the cellular machinery involved in senescence, matrix interaction and response to extrinsic challenges.