Beneficial metabolic effects of PAHSAs depend on the gut microbiota in diet-induced obese mice but not in chow-fed mice.

Dietary lipids play an essential role in regulating the function of the gut microbiota and gastrointestinal tract, and these luminal interactions contribute to mediating host metabolism. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are a family of lipids with antidiabetic and anti-inflammatory properties, but whether the gut microbiota contributes to their beneficial effects on host metabolism is unknown. Here, we report that treating chow-fed female and male germ-free (GF) mice with PAHSAs improves glucose tolerance, but these effects are lost upon high fat diet (HFD) feeding. However, transfer of feces from PAHSA-treated, but not vehicle-treated, chow-fed conventional mice increases insulin sensitivity in HFD-fed GF mice. Thus, the gut microbiota is necessary for, and can transmit, the insulin-sensitizing effects of PAHSAs in HFD-fed GF male mice. Analyses of the cecal metagenome and lipidome of PAHSA-treated mice identified multiple lipid species that associate with the gut commensal Bacteroides thetaiotaomicron (Bt) and with insulin sensitivity resulting from PAHSA treatment. Supplementing live, and to some degree, heat-killed Bt to HFD-fed female mice prevented weight gain, reduced adiposity, improved glucose tolerance, fortified the colonic mucus barrier and reduced systemic inflammation compared to HFD-fed controls. These effects were not observed in HFD-fed male mice. Furthermore, ovariectomy partially reversed the beneficial Bt effects on host metabolism, indicating a role for sex hormones in mediating the Bt probiotic effects. Altogether, these studies highlight the fact that PAHSAs can modulate the gut microbiota and that the microbiota is necessary for the beneficial metabolic effects of PAHSAs in HFD-fed mice.

Laparoscopic vertical sleeve gastrectomy in felines: A cadaveric feasibility study and experimental case series in two cats.

OBJECTIVE: To evaluate the feasibility of laparoscopic vertical sleeve gastrectomy (LVSG) in feline cadavers using endoscopic stapling equipment and report clinical outcomes in two live feline subjects. STUDY DESIGN: Cadaveric study and experimental case series. ANIMALS: Ten feline cadavers; two feline subjects. METHODS: LVSG technique was refined on feline cadavers and included retraction of the liver, dissection of the stomach, assessment of proper location for gastrectomy via stapling, and leak testing. Appropriateness of gastrectomy, gastrectomy %, surgical times and complications were recorded. The procedure was performed on two live feline subjects, and they were followed for 4 months to report surgical complications. RESULTS: LVSG was completed in 9/10 cadavers and both live patients. Stenosis at the incisura was recorded in 2/9 cadavers. No obvious leaks were seen in the 8 cadavers that were tested or either live patient. The mean surgical time for all cadaver procedures and live patients was 110.4 and 115 minutes, respectively. Mean weight of resected cadaver stomach was 10 g and the mean % of the total stomach weight resected was 27.6%. No intra- or postoperative surgical complications occurred in the live subjects. CONCLUSION: LVSG technique appears feasible and safe for use in live patients. CLINICAL RELEVANCE: This LVSG technique may be safely used for partial gastric resection in cats. Further studies are necessary to determine if it is effective at reversing the effects of obesity and diabetes in this population.

Diet-dependent sex differences in the response to vertical sleeve gastrectomy.

Nearly 80% of patients that receive bariatric surgery are women, yet mechanistic preclinical studies have focused on males. The goal of this study was to determine the metabolic impact of diet- and surgery-induced weight loss in males, females, and ovariectomized females. All mice were fed a 60% high-fat diet (HFD) before undergoing either vertical sleeve gastrectomy (VSG) or sham surgery. Mice either remained on an HFD or were switched to a standard chow diet postsurgically. When maintained on an HFD, males and females decreased fat mass and improved oral glucose tolerance after VSG. After dietary intervention, additional adiposity was lost in both surgical groups. Ovariectomized females showed a blunted decrease in fat mass on an HFD, but lost significant adiposity after dietary intervention. Energy expenditure was impacted by dietary and not surgical intervention across all groups. Males decreased hepatic triglyceride levels after VSG, which was further decreased after dietary intervention. Intact and ovariectomized females had a blunted decrease in hepatic triglycerides after VSG, but a significant decrease after dietary intervention. The more pronounced effect of VSG on hepatic lipids in males is strongly associated with changes in hepatic expression of genes and microRNAs previously linked to hepatic lipid regulation and systemic energy homeostasis. These data highlight the importance of postsurgical diet on metabolic outcomes across sexes. Furthermore, these data suggest the impact of VSG on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.NEW & NOTEWORTHY These data highlight the interaction of postsurgical diet after bariatric surgery on metabolic outcomes across sexes. These data suggest the impact of VSG on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.

Hepatocyte p53 ablation induces metabolic dysregulation that is corrected by food restriction and vertical sleeve gastrectomy in mice.

P53 has been implicated in the pathogenesis of obesity and diabetes; however, the mechanisms and tissue sites of action are incompletely defined. Therefore, we investigated the role of hepatocyte p53 in metabolic homeostasis using a hepatocyte-specific p53 knockout mouse model. To gain further mechanistic insight, we studied mice under two complementary conditions of restricted weight gain: vertical sleeve gastrectomy (VSG) or food restriction. VSG or sham surgery was performed in high-fat diet-fed male hepatocyte-specific p53 wild-type and knockout littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Hepatocyte-specific p53 ablation in sham-operated ad libitum-fed mice impaired glucose homeostasis, increased body weight, and decreased energy expenditure without changing food intake. The metabolic deficits induced by hepatocyte-specific p53 ablation were corrected, in part by food restriction, and completely by VSG. Unlike food restriction, VSG corrected the effect of hepatocyte p53 ablation to lower energy expenditure, resulting in a greater improvement in glucose homeostasis compared with food restricted mice. These data reveal an important new role for hepatocyte p53 in the regulation of energy expenditure and body weight and suggest that VSG can improve alterations in energetics associated with p53 dysregulation.

Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge.

Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2-/- and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2-/- mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2-/- mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1 Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.

Rethinking Bile Acid Metabolism and Signaling for Type 2 Diabetes Treatment.

PURPOSE OF REVIEW: Herein, we review the role of FXR and TGR5 in the regulation of hepatic bile acid metabolism, with a focus on how our understanding of bile acid metabolic regulation by these receptors has evolved in recent years and how this improved understanding may facilitate targeting bile acids for type 2 diabetes treatment. RECENT FINDINGS: Bile acid profile is a key regulator of metabolic homeostasis. Inhibition of expression of the enzyme that is required for cholic acid synthesis and thus determines bile acid profile, Cyp8b1, may be an effective target for type 2 diabetes treatment. FXR and, more recently, TGR5 have been shown to regulate bile acid metabolism and Cyp8b1 expression and, therefore, may provide a mechanism with which to target bile acid profile for type 2 diabetes treatment. Inhibition of Cyp8b1 expression is a promising therapeutic modality for type 2 diabetes; however, further work is needed to fully understand the pathways regulating Cyp8b1 expression.

TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice.

OBJECTIVE: Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG. DESIGN: VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5-/- (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed. RESULTS: VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic inflammation and islet morphology after VSG were attenuated in Tgr5-/- relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5-/- relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG. CONCLUSIONS: These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool.

Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes.

The rising prevalence of type-2 diabetes is becoming a pressing issue based on emerging reports that T2DM can also adversely impact mental health. We have utilized the UCD-T2DM rat model in which the onset of T2DM develops spontaneously across time and can serve to understand the pathophysiology of diabetes in humans. An increased insulin resistance index and plasma glucose levels manifested the onset of T2DM. There was a decrease in hippocampal insulin receptor signaling in the hippocampus, which correlated with peripheral insulin resistance index along the course of diabetes onset (r=-0.56, p<0.01). T2DM increased the hippocampal levels of 4-hydroxynonenal (4-HNE; a marker of lipid peroxidation) in inverse proportion to the changes in the mitochondrial regulator PGC-1α. Disrupted energy homeostasis was further manifested by a concurrent reduction in energy metabolic markers, including TFAM, SIRT1, and AMPK phosphorylation. In addition, T2DM influenced brain plasticity as evidenced by a significant reduction of BDNF-TrkB signaling. These results suggest that the pathology of T2DM in the brain involves a progressive and coordinated disruption of insulin signaling, and energy homeostasis, with profound consequences for brain function and plasticity. All the described consequences of T2DM were attenuated by treatment with the glucagon-like peptide-1 receptor agonist, liraglutide. Similar results to those of liraglutide were obtained by exposing T2DM rats to a food energy restricted diet, which suggest that normalization of brain energy metabolism is a crucial factor to counteract central insulin sensitivity and synaptic plasticity associated with T2DM.

Evaluation of plasma inflammatory cytokine concentrations in racing sled dogs.

In human athletes significant changes in cytokine concentrations secondary to exercise have been observed. This prospective study evaluated the effect of a multi-day stage sled dog race on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10). Samples from 20 dogs were harvested prior to and on days 2 and 8 of an 8-day race. Exercise resulted in significantly decreased TNF-α and IL-8 as well as increases of MCP-1, IL-6, and IL-10 concentrations (P-value between 0.01 and < 0.0001 for all parameters). The proportion of values for IL-2 that were below the detection limit increased from 40% on day 0 to 75% on day 2 and decreased on day 8 to 40% (P = 0.04). Racing sled dogs show cytokine-concentration changes that are different from those in humans.

Évaluation des concentrations plasmatiques de cytokines inflammatoires chez des chiens de traîneau de course. Chez les athlètes humains, des changements importants des concentrations de cytokines secondaires à l'exercice ont été observés. Cette étude prospective a évalué l'effet d'une course de chiens de traîneau par étapes de plusieurs jours sur les concentrations plasmatiques des protéines-1 chimio-attractives des monocytes (MCP-1), du facteur-alpha nécrosant des tumeurs (TNF-α), d'interleukine-2 (IL-2), d'interleukine-6 (IL-6), d'interleukine-8 (IL-8) et d'interleukine-10 (IL-10). Des échantillons ont été prélevés sur 20 chiens avant la course et aux jours 2 et 8 d'une course de 8 jours. L'exercice a produit des valeurs significativement réduites de TNF-α et d'IL-8 ainsi qu'une hausse des concentrations de MCP-1, d'IL-6 et d'IL-10 (la valeur-P entre 0,01 et < 0,0001 pour tous les paramètres). La proportion des valeurs pour IL-2 qui étaient inférieures au seuil de détection a augmenté de 40 % le jour 0 à 75 % le jour 2 et a baissé le jour 8 à 40 % (P = 0,04). Les chiens de traîneau de course montrent des changements de la concentration des cytokines qui sont différents de ceux observés chez les humains.(Traduit par Isabelle Vallières).

Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation.

Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and adiposity and is a drug target for the treatment of obesity and diabetes. Here we identify pyruvate kinase M2 (PKM2) as a novel PTP1B substrate in adipocytes. PTP1B deficiency leads to increased PKM2 total tyrosine and Tyr(105) phosphorylation in cultured adipocytes and in vivo. Substrate trapping and mutagenesis studies identify PKM2 Tyr-105 and Tyr-148 as key sites that mediate PTP1B-PKM2 interaction. In addition, in vitro analyses illustrate a direct effect of Tyr-105 phosphorylation on PKM2 activity in adipocytes. Importantly, PTP1B pharmacological inhibition increased PKM2 Tyr-105 phosphorylation and decreased PKM2 activity. Moreover, PKM2 Tyr-105 phosphorylation is regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, decreased PKM2 Tyr-105 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Together, these findings identify PKM2 as a novel substrate of PTP1B and provide new insights into the regulation of adipose PKM2 activity.

Fish oil supplementation ameliorates fructose-induced hypertriglyceridemia and insulin resistance in adult male rhesus macaques.

Fish oil (FO) is a commonly used supplemental source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), 2 n-3 (ω-3) polyunsaturated fatty acids (PUFAs) that have been shown to have a variety of health benefits considered to be protective against cardiometabolic diseases. Although the effects of EPA and DHA on lipid metabolism have been extensively studied, not all of the metabolic effects of FO-derived n-3 PUFAs have been characterized. Our laboratory recently showed that a high-fructose diet in rhesus monkeys induces the features of metabolic syndrome (MetS) similar to those observed in humans. Thus, we specifically wanted to evaluate the effects of FO in rhesus monkeys fed a high-fructose diet and hypothesized that FO supplementation would mitigate the development of fructose-induced insulin resistance, dyslipidemia, and other cardiometabolic risk factors. In this study, adult monkeys (aged 12-20 y) received either a standard unpurified diet plus 75 g fructose/d (control group; n = 9) or a standard unpurified diet, 75 g fructose/d, and 4 g FO (16% EPA + 11% DHA)/d (treatment group; n = 10) for 6 mo. Importantly, our results showed that daily FO supplementation in the monkeys prevented fructose-induced hypertriglyceridemia and insulin resistance as assessed by intravenous-glucose-tolerance testing (P ≤ 0.05). Moreover, FO administration in the monkeys prevented fructose-induced increases in plasma apolipoprotein (Apo)C3, ApoE, and leptin concentrations and attenuated decreases in circulating adropin concentrations (P ≤ 0.05). No differences between the control and FO-treated monkeys were observed in body weight, lean mass, fat mass, or fasting glucose, insulin, and adiponectin concentrations. In conclusion, FO administration in a nonhuman primate model of diet-induced MetS ameliorates many of the adverse changes in lipid and glucose metabolism induced by chronic fructose consumption.

Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats.

Leptin has been shown to reduce hyperglycemia in rodent models of type 1 diabetes. We investigated the effects of leptin administration in University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rats, which develop adult-onset polygenic obesity and type 2 diabetes. Animals that had been diabetic for 2 mo were treated with s.c. injections of saline (control) or murine leptin (0.5 mg/kg) twice daily for 1 mo. Control rats were pair-fed to leptin-treated animals. Treatment with leptin normalized fasting plasma glucose and was accompanied by lowered HbA1c, plasma glucagon, and triglyceride concentrations and expression of hepatic gluconeogenic enzymes compared with vehicle (P < 0.05), independent of any effects on body weight and food intake. In addition, leptin-treated animals exhibited marked improvement of insulin sensitivity and glucose homeostasis compared with controls, whereas pancreatic insulin content was 50% higher in leptin-treated animals (P < 0.05). These effects coincided with activation of leptin and insulin signaling pathways and down-regulation of the PKR-like endoplasmic reticulum (ER) kinase/eukaryotic translation inhibition factor 2α (PERK-eIF2α) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased pro-opiomelanocortin and decreased agouti-related peptide in the hypothalamus. In contrast, several markers of inflammation/immune function were elevated with leptin treatment in the same tissues (P < 0.05), suggesting that the leptin-mediated increase of insulin sensitivity was not attributable to decreased inflammation. Thus, leptin administration improves insulin sensitivity and normalizes fasting plasma glucose in diabetic UCD-T2DM rats, independent of energy intake, via peripheral and possibly centrally mediated actions, in part by decreasing circulating glucagon and ER stress.

Vertical Sleeve Gastrectomy Reduces Gut Luminal Deoxycholic Acid Concentrations in Mice.

BACKGROUND: Bariatric surgery alters bile acid metabolism, which contributes to post-operative improvements in metabolic health. However, the mechanisms by which bariatric surgery alters bile acid metabolism are incompletely defined. In particular, the role of the gut microbiome in the effects of bariatric surgery on bile acid metabolism is incompletely understood. Therefore, we sought to define the changes in gut luminal bile acid composition after vertical sleeve gastrectomy (VSG). METHODS: Bile acid profile was determined by UPLC-MS/MS in serum and gut luminal samples from VSG and sham-operated mice. Sham-operated mice were divided into two groups: one was fed ad libitum, while the other was food-restricted to match their body weight to the VSG-operated mice. RESULTS: VSG decreased gut luminal secondary bile acids, which was driven by a decrease in gut luminal deoxycholic acid concentrations and abundance. However, gut luminal cholic acid (precursor for deoxycholic acid) concentration and abundance did not differ between groups. Therefore, the observed decrease in gut luminal deoxycholic acid abundance after VSG was not due to a reduction in substrate availability. CONCLUSION: VSG decreased gut luminal deoxycholic acid abundance independently of body weight, which may be driven by a decrease in gut bacterial bile acid metabolism.

Correction: Deoxycholic acid supplementation impairs glucose homeostasis in mice.

[This corrects the article DOI: 10.1371/journal.pone.0200908.].

Glucagon infusion alters the circulating metabolome and urine amino acid excretion in dogs.

Glucagon plays a central role in amino acid (AA) homeostasis. The dog is an established model of glucagon biology, and recently, metabolomic changes in people associated with glucagon infusions have been reported. Glucagon also has effects on the kidney; however, changes in urinary AA concentrations associated with glucagon remain under investigation. Therefore, we aimed to fill these gaps in the canine model by determining the effects of glucagon on the canine plasma metabolome and measuring urine AA concentrations. Employing two constant rate glucagon infusions (CRI) - low-dose (CRI-LO: 3 ng/kg/min) and high-dose (CRI-HI: 50 ng/kg/min) on five research beagles, we monitored interstitial glucose and conducted untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) on plasma samples and urine AA concentrations collected pre- and post-infusion. The CRI-HI induced a transient glucose peak (90-120 min), returning near baseline by infusion end, while only the CRI-LO resulted in 372 significantly altered plasma metabolites, primarily reductions (333). Similarly, CRI-HI affected 414 metabolites, with 369 reductions, evidenced by distinct clustering post-infusion via data reduction (PCA and sPLS-DA). CRI-HI notably decreased circulating AA levels, impacting various AA-related and energy-generating metabolic pathways. Urine analysis revealed increased 3-methyl-l-histidine and glutamine, and decreased alanine concentrations post-infusion. These findings demonstrate glucagon's glucose-independent modulation of the canine plasma metabolome and highlight the dog's relevance as a translational model for glucagon biology. Understanding these effects contributes to managing dysregulated glucagon conditions and informs treatments impacting glucagon homeostasis.

Bariatric Surgery Is Associated with Lower Concentrations of Fecal Secondary Bile Acids and Their Metabolizing Microbial Enzymes: A Pilot Study.

INTRODUCTION: Excess body fat elevates colorectal cancer risk. While bariatric surgery (BRS) induces significant weight loss, its effects on the fecal stream and colon biology are poorly understood. Specifically, limited data exist on the impact of bariatric surgery (BRS) on fecal secondary bile acids (BA), including lithocholic acid (LCA), a putative promotor of colorectal carcinogenesis. METHODS: This cross-sectional case-control study included 44 patients with obesity; 15 pre-BRS (controls) vs. 29 at a median of 24.1 months post-BRS. We examined the fecal concentrations of 11 BA by liquid chromatography and gene abundance of BA-metabolizing bacterial enzymes through fecal metagenomic sequencing. Differences were quantified using non-parametric tests for BA levels and linear discriminant analysis (LDA) effect size (LEfSe) for genes encoding BA-metabolizing enzymes. RESULTS: Total fecal secondary BA concentrations trended towards lower levels post- vs. pre-BRS controls (p = 0.07). Individually, fecal LCA concentrations were significantly lower post- vs. pre-BRS (8477.0 vs. 11,914.0 uM/mg, p < 0.008). Consistent with this finding, fecal bacterial genes encoding BA-metabolizing enzymes, specifically 3-betahydroxycholanate-3-dehydrogenase (EC 1.1.1.391) and 3-alpha-hydroxycholanate dehydrogenase (EC 1.1.1.52), were also lower post- vs. pre-BRS controls (LDA of - 3.32 and - 2.64, respectively, adjusted p < 0.0001). Post-BRS fecal BA concentrations showed significant inverse correlations with weight loss, a healthy diet quality, and increased physical activity. CONCLUSIONS: Concentrations of LCA, a secondary BA, and bacterial genes needed for BA metabolism are lower post-BRS. These changes can impact health and modulate the colorectal cancer cascade. Further research is warranted to examine how surgical alterations and the associated dietary changes impact bile acid metabolism.

Dietary resistant starch supplementation increases gut luminal deoxycholic acid abundance in mice.

Bile acids (BA) are among the most abundant metabolites produced by the gut microbiome. Primary BAs produced in the liver are converted by gut bacterial 7-α-dehydroxylation into secondary BAs, which can differentially regulate host health via signaling based on their varying affinity for BA receptors. Despite the importance of secondary BAs in host health, the regulation of 7-α-dehydroxylation and the role of diet in modulating this process is incompletely defined. Understanding this process could lead to dietary guidelines that beneficially shift BA metabolism. Dietary fiber regulates gut microbial composition and metabolite production. We tested the hypothesis that feeding mice a diet rich in a fermentable dietary fiber, resistant starch (RS), would alter gut bacterial BA metabolism. Male and female wild-type mice were fed a diet supplemented with RS or an isocaloric control diet (IC). Metabolic parameters were similar between groups. RS supplementation increased gut luminal deoxycholic acid (DCA) abundance. However, gut luminal cholic acid (CA) abundance, the substrate for 7-α-dehydroxylation in DCA production, was unaltered by RS. Further, RS supplementation did not change the mRNA expression of hepatic BA producing enzymes or ileal BA transporters. Metagenomic assessment of gut bacterial composition revealed no change in the relative abundance of bacteria known to perform 7-α-dehydroxylation. P. ginsenosidimutans and P. multiformis were positively correlated with gut luminal DCA abundance and increased in response to RS supplementation. These data demonstrate that RS supplementation enriches gut luminal DCA abundance without increasing the relative abundance of bacteria known to perform 7-α-dehydroxylation.

Is 14-3-3 the Combination to Unlock New Pathways to Improve Metabolic Homeostasis and ß-Cell Function?

Since their discovery nearly five decades ago, molecular scaffolds belonging to the 14-3-3 protein family have been recognized as pleiotropic regulators of diverse cellular and physiological functions. With their ability to bind to proteins harboring specific serine and threonine phosphorylation motifs, 14-3-3 proteins can interact with and influence the function of docking proteins, enzymes, transcription factors, and transporters that have essential roles in metabolism and glucose homeostasis. Here, we will discuss the regulatory functions of 14-3-3 proteins that will be of great interest to the fields of metabolism, pancreatic ß-cell biology, and diabetes. We first describe how 14-3-3 proteins play a central role in glucose and lipid homeostasis by modulating key pathways of glucose uptake, glycolysis, oxidative phosphorylation, and adipogenesis. This is followed by a discussion of the contributions of 14-3-3 proteins to calcium-dependent exocytosis and how this relates to insulin secretion from ß-cells. As 14-3-3 proteins are major modulators of apoptosis and cell cycle progression, we will explore if 14-3-3 proteins represent a viable target for promoting ß-cell regeneration and discuss the feasibility of targeting 14-3-3 proteins to treat metabolic diseases such as diabetes. ARTICLE HIGHLIGHTS: 14-3-3 proteins are ubiquitously expressed scaffolds with multiple roles in glucose homeostasis and metabolism. 14-3-3ζ regulates adipogenesis via distinct mechanisms and is required for postnatal adiposity and adipocyte function. 14-3-3ζ controls glucose-stimulated insulin secretion from pancreatic ß-cells by regulating mitochondrial function and ATP synthesis as well as facilitating cross talk between ß-cells and α-cells.

Plasma concentrations of glucagon and glucagon-like peptide-1 are reduced in dogs with aminoaciduric canine hypoaminoacidemic hepatopathy syndrome versus healthy dogs: a preliminary study.

OBJECTIVE: To compare plasma concentrations of glucagon and glucagon-like peptide-1 (GLP-1) between healthy dogs and dogs with aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES) dogs. ANIMALS: Privately owned healthy (n = 5) control (CON) and ACHES (8; including 3 with diabetes mellitus) dogs enrolled between October 2, 2019, and March 4, 2020. PROCEDURES: This was a prospective case-control study. Fasting and 15-minute postprandial plasma glucagon total GLP-1 concentrations were measured with commercial immunoassays. RESULTS: Dogs with ACHES had lower fasting (median, 0.5; mean difference, 3.8; 95% CI, 0.52 to 7.0 pmol/L; P = .021) and postprandial (median, 0.35; mean difference, 5.0; 95% CI, 1.8 to 8.3 pmol/L; P = .002) plasma glucagon concentrations than CON (fasting and postprandial medians, 3.5 and 4.6 pmol/L, respectively). ACHES dogs had significantly (median, 4.15; mean difference, 12.65; 95% CI, 2.0 to 16.3 pg/ml; P = .011) lower postprandial plasma GLP-1 concentrations than CON (median, 16.8 pg/ml). There was no significant difference between fasting GLP-1 levels between the 2 groups. CLINICAL RELEVANCE: Lower postprandial plasma GLP-1 concentrations may contribute to the propensity of diabetes mellitus in ACHES. Lower glucagon concentrations may reflect an appropriate physiologic response to hypoaminoacidemia.