Nutrition & Metabolism[JOURNAL]
Sun
200 papers
β-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum.
Kim JY, Tfayli H, Bacha F … +3 more , Lee S, Gebara N, Arslanian S
Metabolism · 2020 Nov · PMID 32835760 · Full text
BACKGROUND/AIMS: In obese youth, it is not clear what degree of β-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to ty...
BACKGROUND/AIMS: In obese youth, it is not clear what degree of β-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes. We aimed to investigate the quantitative relationship between β-cell (clamp-measured disposition index [DI]) and OGTT glucose area under the curve (G-AUC) in obese youth across the spectrum of glucose tolerance. METHODS: Data from 152 youth (58 African-American [AA] and 94 American-White [AW]; 73 NGT, 48 IGT, and 31 type 2 diabetes) who completed a 3-h hyperinsulinemic (80 mu/m/min)-euglycemic clamp, and a 2-h hyperglycemic (225 mg/dL) clamp synchronized with a 2-h OGTT were examined. RESULTS: In IGT vs. NGT, 36% lower DI corresponded to 27% higher G-AUC; in type 2 diabetes vs. IGT, 65% lower DI related to 25% higher G-AUC, and in type 2 diabetes vs. NGT, 78% lower DI paralleled 59% higher G-AUC. Although AA vs. AW youth had larger decrements in DI, from NGT to IGT and from NGT to type 2 diabetes, they displayed comparable increments in G-AUC. CONCLUSION: At least ~35-50% recovery in β-cell function might be needed to have clinically meaningful improvement in G-AUC commensurate with conversion to better glucose tolerance. Mechanism(s) protective against dysglycemia might be operative in AA vs. AW youth despite greater declines in DI. Treatments aiming to improve β-cell function should focus on degree of change in DI commensurate with clinically meaningful changes in glycemia, reflective of restoration of glucose tolerance.
Absence of AGPAT2 impairs brown adipogenesis, increases IFN stimulated gene expression and alters mitochondrial morphology.
Tapia PJ, Figueroa AM, Eisner V … +5 more , González-Hódar L, Robledo F, Agarwal AK, Garg A, Cortés V
Metabolism · 2020 Oct · PMID 32810486 · Publisher ↗
BACKGROUND: Biallelic loss of function variants in AGPAT2, encoding 1-acylglycerol-3-phosphate O-acyltransferase 2, cause congenital generalized lipodystrophy type 1, a disease characterized by near total loss of white a...
BACKGROUND: Biallelic loss of function variants in AGPAT2, encoding 1-acylglycerol-3-phosphate O-acyltransferase 2, cause congenital generalized lipodystrophy type 1, a disease characterized by near total loss of white adipose tissue and metabolic complications. Agpat2 deficient (Agpat2) mice completely lacks both white and interscapular brown adipose tissue (iBAT). The objective of the present study was to characterize the effects of AGPAT2 deficiency in brown adipocyte differentiation. METHODS: Preadipocytes obtained from newborn (P0.5) Agpat2 and wild type mice iBAT were differentiated into brown adipocytes, compared by RNA microarray, RT-qPCR, High-Content Screening (HCS), western blotting and electron microscopy. RESULTS: 1) Differentiated Agpat2 brown adipocytes have fewer lipid-laden cells and lower abundance of Pparγ, Pparα, C/ebpα and Pgc1α, both at the mRNA and protein levels, compared those to wild type cells. Prmd16 levels were equivalent in both, Agpat2 and wild type, while Ucp1 was only induced in wild type cells, 2) These differences were not due to lower abundance of preadipocytes, 3) Differentiated Agpat2 brown adipocytes are enriched in the mRNA abundance of genes participating in interferon (IFN) type I response, whereas genes involved in mitochondrial homeostasis were decreased, 4) Mitochondria in differentiated Agpat2 brown adipocytes had altered morphology and lower mass and contacting sites with lipid droplets concomitant with lower levels of Mitofusin 2 and Perlipin 5. CONCLUSION: AGPAT2 is necessary for normal brown adipose differentiation. Its absence results in a lower proportion of lipid-laden cells, increased expression of interferon-stimulated genes (ISGs) and alterations in mitochondrial morphology, mass and fewer mitochondria to lipid droplets contacting sites in differentiated brown adipocytes.
Cardiovascular outcomes trials with incretin-based medications: a critical review of data available on GLP-1 receptor agonists and DPP-4 inhibitors.
Sachinidis A, Nikolic D, Stoian AP … +4 more , Papanas N, Tarar O, Rizvi AA, Rizzo M
Metabolism · 2020 Oct · PMID 32810485 · Publisher ↗
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are so called "incretin-based therapies" (IBTs) that represent innovative therapeutic approaches and are commonly used in...
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are so called "incretin-based therapies" (IBTs) that represent innovative therapeutic approaches and are commonly used in clinical practice for the treatment of type 2 diabetes mellitus (T2DM). The cardiovascular outcome trials (CVOTs) have provided useful information that has helped to shape changes in clinical practice guidelines for the management of T2DM. At the same time, the mechanisms that may explain the nonglycemic and cardiovascular (CV) benefits of these medications are still being explored. A summary of the main findings from CVOTs performed to-date with particular emphasis on various outcomes and inconsistencies observed in the trials is provided. Overall, available data is favourable to the early deployment of GLP-1RAs in clinical practice, fully in line with recommendations from international scientific guidelines, and based on their effects on glucose metabolism parameters, body weight reduction and CV outcomes. Evidence further suggest that the CV benefits of GLP-1RAs may not be a class effect, with GLP-1 analogues having a greater benefit rather than exendin-based agents.
commentary: COVID-19 and Obesity: Exploring Biologic Vulnerabilities, Structural Disparities, and Weight Stigma.
Townsend MJ, Kyle TK, Stanford FC
Metabolism · 2020 Sep · PMID 32673650 · Full text
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SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes.
Li H, Wang D, Wu H … +7 more , Shen H, Lv D, Zhang Y, Lu H, Yang J, Tang Y, Li M
Metabolism · 2020 Sep · PMID 32621820 · Publisher ↗
BACKGROUND: Iron is finely regulated due to its vital roles in organisms and the peroxidase reactivity if excess. Solute Carrier Family 46 Member 1 (SLC46A1), also named PCFT or HCP1, is the main importer of heme‑iron in...
BACKGROUND: Iron is finely regulated due to its vital roles in organisms and the peroxidase reactivity if excess. Solute Carrier Family 46 Member 1 (SLC46A1), also named PCFT or HCP1, is the main importer of heme‑iron in the intestine, but has a high abundance in the liver. Since the liver has a central role in iron homeostasis, whether SLC46A1 regulates hepatic iron metabolism is of interest to be identified. METHODS: The recombinant adeno-associated virus vectors were used to hepatic-specifically inhibit SLC46A1 expression to observe its effects on hepatic iron metabolism. Then the abilities of SLC46A1 in importing heme and folate, and consequent alterations of iron content in hepatocytes were determined. Furthermore, effects of iron on SLC46A1 expression were investigated both in vitro and in vivo. RESULTS: The hepatocyte-specific inhibition of SLC46A1 decreases iron content in the liver and increases iron content in serum. Expressions of iron-related molecules, transferrin receptor 1, hepcidin and ferroportin, are correspondingly altered. Interestingly, free heme concentration in serum is increased, indicating a decreased import of heme by the liver. In hepatocytes, SLC46A1 is capable of importing hemin, increasing intracellular iron content. The import of hemin by SLC46A1 is unaffected by its other substrate, folate. Instead, hemin treatment decreases SLC46A1 expression, reducing the import of folate. In addition, SLC46A1 itself shows to be iron-responsive both in vivo and in vitro, making it available for regulating iron metabolism. CONCLUSION: The results elucidate that SLC46A1 regulates iron metabolism in the liver through a folate-independent manner of importing heme. The iron-responsive characters of SLC46A1 give us a new clue to link heme or iron overload with folate deficiency diseases.
The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes.
Stoian AP, Sachinidis A, Stoica RA … +3 more , Nikolic D, Patti AM, Rizvi AA
Metabolism · 2020 Aug · PMID 32553739 · Publisher ↗
INTRODUCTION: The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabete...
INTRODUCTION: The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents. OBJECTIVE: This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review. DISCUSSION: DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer. CONCLUSION: Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.
Fortifying diet with rapeseed oil instead of butterfat attenuates the progression of diet-induced non-alcoholic fatty liver disease (NAFLD) and impairment of glucose tolerance.
Brandt A, Rajcic D, Jin CJ … +6 more , Sánchez V, Engstler AJ, Jung F, Nier A, Baumann A, Bergheim I
Metabolism · 2020 Aug · PMID 32497536 · Publisher ↗
BACKGROUND: Absolute dietary fat intake but even more so fatty acid pattern is discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined if switching a butterfat enrich...
BACKGROUND: Absolute dietary fat intake but even more so fatty acid pattern is discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined if switching a butterfat enriched diet to a rapeseed oil (RO) enriched diet affects progression of an existing NAFLD and glucose intolerance in mice. METHODS: For eight weeks, female C57Bl/6J mice were either fed a liquid control (C) or a butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% butterfat) to induce early signs of steatohepatitis and glucose intolerance in mice. For additional five weeks mice received either BFC or C or a fat-, fructose- and cholesterol-rich and control diet, in which butterfat was replaced with RO (ROFC and CRO). Markers of glucose metabolism, liver damage and intestinal barrier were assessed. RESULTS: Exchanging butterfat with RO attenuated the progression of BFC diet-induced NAFLD and glucose intolerance. Beneficial effects of RO were associated with lower portal endotoxin levels and an attenuation of the induction of the toll-like receptor-4-dependent signaling cascades in liver. Peroxisome proliferator-activated receptor γ activity was induced in small intestine of ROFC-fed mice. CONCLUSION: Taken together, exchanging butterfat with RO attenuated the progression of diet-induced steatohepatitis and glucose intolerance in mice.
Impact of antidiabetic agents on dementia risk: A Bayesian network meta-analysis.
Zhou JB, Tang X, Han M … +2 more , Yang J, Simó R
Metabolism · 2020 Aug · PMID 32446679 · Publisher ↗
BACKGROUND: Dementia is more prevalent among people with type 2 diabetes, but little is known regarding the influence of antidiabetic agents on this association. OBJECTIVE: This study assessed the impact of various antid...
BACKGROUND: Dementia is more prevalent among people with type 2 diabetes, but little is known regarding the influence of antidiabetic agents on this association. OBJECTIVE: This study assessed the impact of various antidiabetic agents on the risk of dementia among patients with Type 2 diabetes mellitus. METHODS: Relevant studies were retrieved from the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases. Nine antidiabetic agents were included in the search. Data were pooled via network meta-analysis and meta-analysis. RESULTS: Nine studies were selected for the network meta-analysis with 530,355 individuals and 17 studies for the meta-analysis with 1,258,879 individuals. The analysis excluded glucagon-like peptide 1 (GLP-1) analogs and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors due to the absence of relevant data. The use of dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, thiazolidinedione, and sulfonylurea was associated with a decreased risk of dementia in comparison to no treatment with antidiabetic agents (hazard ratio [HR] for DPP-4 inhibitors, 0.54; 95% confidence interval [CI], 0.38-0.74, HR for metformin, 0.75; 95% CI, 0.63-0.86; HR for sulfonylurea, 0.85; 95%CI, 0.73-0.98 and HR for thiazolidinedione, 0.70; 95% CI, 0.55-0.89, respectively). However, the node-splitting analysis showed the inconsistency of direct and indirect estimates in sulfonylurea (P = 0.042). DPP-4 inhibitors, metformin, thiazolidinedione, and sulfonylurea exhibited a significant impact on the risk of dementia in diabetics compared with insulin (HR, 0.35; 95%CI, 0.20-0.59, HR, 0.48; 95% CI, 0.30-0.77, HR, 0.45; 95% CI, 0.29-0.73 and HR, 0.55; 95% CI, 0.34-0.88, respectively). DPP-4 inhibitors also exhibited a protective effect on the risk of Alzheimer's dementia compared with the no treatment with antidiabetic agents (HR, 0.48; 95% CI, 0.25-0.92). The meta-analysis demonstrated a protective effect of using metformin and DPP-4 inhibitors on the risk of dementia (HR, 0.86; 95% CI, 0.74-1.00 and HR, 0.65; 95% CI, 0.55-0.76, respectively). Further analysis showed insulin was associated with an increased risk of Alzheimer's dementia (HR, 1.60; 95% CI, 1.13-2.26). Only two case-control studies mentioned GLP-1 analogs and SGLT-2 inhibitors, and the pooled ORs showed no evidence of an association with dementia (GLP-1 analogs: 0.71; 95% CI, 0.46-1.10 and SGLT-2 inhibitors: 0.74; 95% CI, 0.47-1.15). CONCLUSION: This analysis indicated that patients with type 2 diabetes under treatment with DPP-4 inhibitors presented with the lowest risk of dementia, followed by those treated with metformin and thiazolidinedione, while treatment with insulin was associated with the highest risk. For the increasing focus on the protective effect on dementia, further specific clinical studies are needed to evaluate the impact of GLP-1 analogs and SGLT-2 inhibitors on the risk of dementia.
FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes.
Frühbeck G, Fernández-Quintana B, Paniagua M … +10 more , Hernández-Pardos AW, Valentí V, Moncada R, Catalán V, Becerril S, Gómez-Ambrosi J, Portincasa P, Silva C, Salvador J, Rodríguez A
Metabolism · 2020 Jul · PMID 32407726 · Publisher ↗
BACKGROUND: Fibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin...
BACKGROUND: Fibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue. METHODS: Plasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study. RESULTS: Plasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markers PRDM16, TMEM26 and CD137. Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1 and NRF2). Human FNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis. CONCLUSIONS: Taken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.
The effect of underweight on female and male reproduction.
Boutari C, Pappas PD, Mintziori G … +4 more , Nigdelis MP, Athanasiadis L, Goulis DG, Mantzoros CS
Metabolism · 2020 Jun · PMID 32289345 · Publisher ↗
Chronic energy deficiency can impair the hypothalamic-pituitary-gonadal (HPG) axis and lead to hypothalamic anovulation in underweight women. This review presents the syndromes related to underweight status that are asso...
Chronic energy deficiency can impair the hypothalamic-pituitary-gonadal (HPG) axis and lead to hypothalamic anovulation in underweight women. This review presents the syndromes related to underweight status that are associated with infertility, summarizes the underlying mechanisms, and reviews the available treatment options. Eating disorders, such as anorexia nervosa (AN), constitute the most common cause of infertility in underweight women, who, in addition, experience miscarriages, and sexual dysfunction. The relative energy deficiency in sports (RED-S; former terminology: athlete's triad) involves menstrual dysfunction due to low energy availability, which results in anovulation. Moreover, lipodystrophies, malnutrition, starvation, systematic illnesses (malignancies, endocrinopathies, infectious diseases, advanced chronic diseases, neurologic illnesses), and the utilization of drugs can cause excessive weight loss. They may result in fertility problems due to the loss of adipose tissue and the subsequent hormonal disturbances. Each of these conditions requires multidisciplinary management. Nutritional counseling should target the restoration of energy balance by increasing intake and reducing output. Medical treatment, recommended only for patients who did not respond to standard treatment, may include antipsychotics, antidepressants, or leptin administration. Finally, psychiatric treatment is considered an integral part of the standard treatment.
PCSK9 Inhibition with alirocumab increases the catabolism of lipoprotein(a) particles in statin-treated patients with elevated lipoprotein(a).
Watts GF, Chan DC, Pang J … +5 more , Ma L, Ying Q, Aggarwal S, Marcovina SM, Barrett PHR
Metabolism · 2020 Jun · PMID 32240727 · Publisher ↗
BACKGROUND: Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an i...
BACKGROUND: Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD. METHODS: The effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (>0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment. RESULTS: Alirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P< 0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P <0.001) and increased the FCR of apo(a) (+28%, P< 0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P< 0.001). CONCLUSIONS: In statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.
The protein S100A4 as a novel marker of insulin resistance in prepubertal and pubertal children with obesity.
Anguita-Ruiz A, Mendez-Gutierrez A, Ruperez AI … +8 more , Leis R, Bueno G, Gil-Campos M, Tofe I, Gomez-Llorente C, Moreno LA, Gil Á, Aguilera CM
Metabolism · 2020 Apr · PMID 32084430 · Publisher ↗
BACKGROUND: S100A4 is a metastasis-associated protein also reported as a promising marker for dysfunctional white adipose tissue (WAT) and insulin resistance (IR) in adult and adolescent populations. OBJECTIVE: We aimed...
BACKGROUND: S100A4 is a metastasis-associated protein also reported as a promising marker for dysfunctional white adipose tissue (WAT) and insulin resistance (IR) in adult and adolescent populations. OBJECTIVE: We aimed to evaluate the association between the protein S100A4 and obesity and IR in children and during pubertal development. DESIGN AND METHODS: The study design consisted of three cross-sectional populations of 249, 11 and 19 prepubertal children respectively (named study population 1, 2 and 3), and a longitudinal population of 53 girls undergoing sexual maturation (study population 4). All subjects were classified into experimental groups according to their sex, obesity and IR status. All study populations counted on anthropometry, glucose, and lipid metabolism, inflammation and cardiovascular biomarkers as well as S100A4 plasma levels measured. The study population 1 was intended as the discovery population in which to elucidate the relationship between Obesity-IR and S100A4 plasma levels in prepubertal children. The cross-sectional populations 2 and 3 further counted on WAT gene expression data for investigating the molecular basis of this association. Instead, the longitudinal study population 4 presented blood whole-genome DNA methylation data at each temporal record, allowing deepening into the Obesity-IR-S1004 relationship during puberty as well as deciphering plausible epigenetic mechanisms altering S100A4 plasma levels. RESULTS: S100A4 plasma levels were strongly associated with several metabolic and anthropometric outcomes, namely IR, in prepubertal non-diabetic obese children. We also found highly significant positive associations during the course of puberty between the increase in S100A4 levels and the increase in HOMA-IR (P = 0.0003, FDR = 0.005) and insulin levels (P = 0.0003, FDR = 0.005). Methylation in two-enhancer related CpG sites of the S100A4 region (cg07245635 and cg10447638) was associated with IR biomarkers at the prepubertal stage and with longitudinal changes in these measurements. We further reported an association between visceral WAT (vWAT) S100A4 expression and HOMA-IR, insulin levels and BMI Z-Score, but not with circulating S100A4. CONCLUSIONS: We report for the first time the association of S100A4 with IR and WAT dysfunction in prepubertal populations as well as how the change in plasma S100A4 levels accompanies longitudinal trajectories of IR in children during pubertal development. Moreover, we propose epigenetic changes in two methylation sites and an altered S100A4 vWAT expression as plausible molecular mechanisms underlying this disturbance in obesity.
mTORC1-dependent protein synthesis and autophagy uncouple in the regulation of Apolipoprotein A-I expression.
Georgila K, Gounis M, Havaki S … +2 more , Gorgoulis VG, Eliopoulos AG
Metabolism · 2020 Apr · PMID 32084429 · Publisher ↗
BACKGROUND: Apolipoprotein A-I (ApoA-I) is involved in reverse cholesterol transport as a major component of HDL, but also conveys anti-thrombotic, anti-oxidative, anti-inflammatory and immune-regulatory properties that...
BACKGROUND: Apolipoprotein A-I (ApoA-I) is involved in reverse cholesterol transport as a major component of HDL, but also conveys anti-thrombotic, anti-oxidative, anti-inflammatory and immune-regulatory properties that are pertinent to its protective roles in cardiovascular, inflammatory and malignant pathologies. Despite the pleiotropy in ApoA-I functions, the regulation of intracellular ApoA-I levels remains poorly explored. METHODS: HepG2 hepatoma cells and primary mouse hepatocytes were used as in vitro models to study the impact of genetic and chemical inhibitors of autophagy and the proteasome on ApoA-I by immunoblot, immunofluorescence and electron microscopy. Different growth conditions were implemented in conjunction with mTORC inhibitors to model the influence of nutrient scarcity versus sufficiency on ApoA-I regulation. Hepatic ApoA-I expression was also evaluated in high fat diet-fed mice displaying blockade in autophagy. RESULTS: Under nutrient-rich conditions, basal ApoA-I levels in liver cells are sustained by the balancing act of autophagy and of mTORC1-dependent de novo protein synthesis. ApoA-I proteolysis occurs through a canonical autophagic pathway involving Beclin1 and ULK1 and the receptor protein p62/SQSTM1 that targets ApoA-I to autophagosomes. However, upon aminoacid insufficiency, suppression of ApoA-I synthesis prevails, rendering mTORC1 inactivation dispensable for autophagy-mediated ApoA-I proteolysis. CONCLUSION: These data underscore the major contribution of post-transcriptional mechanisms to ApoA-I levels which differentially involve mTORC1-dependent signaling to protein synthesis and autophagy, depending on nutrient availability. Given the established role of ApoA-I in HDL-mediated reverse cholesterol transport, this mode of ApoA-I regulation may reflect a hepatocellular response to the organismal requirement for maintenance of cholesterol and lipid reserves under conditions of nutrient scarcity.
Complications, morbidity and mortality of nonalcoholic fatty liver disease.
Mantovani A, Scorletti E, Mosca A … +3 more , Alisi A, Byrne CD, Targher G
Metabolism · 2020 Oct · PMID 32006558 · Publisher ↗
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized public health problem, affecting up to a quarter of the world's adult population. The burden of NAFLD is influenced by the epidemics of obesity and t...
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized public health problem, affecting up to a quarter of the world's adult population. The burden of NAFLD is influenced by the epidemics of obesity and type 2 diabetes mellitus (T2DM) and the prevalence of these conditions is not expected to decrease in the forthcoming decades. Consequently, the burden of NAFLD-related liver complications (non-alcoholic steatohepatitis [NASH], cirrhosis and hepatocellular carcinoma) and the need for life-saving liver transplantation are also expected to increase further in the near future. A large body of clinical evidence indicates that NAFLD is associated not only with increased liver-related morbidity and mortality, but also with an increased risk of developing other important extra-hepatic diseases, such as cardiovascular disease (that is the predominant cause of death in patients with NAFLD), extra-hepatic cancers (mainly colorectal cancers), T2DM and chronic kidney disease. Thus, NAFLD creates a considerable health and economic burden worldwide and often results in poor quality of life. This narrative review provides an overview of the current literature on main complications, morbidity and mortality of this common and burdensome liver disease.
Sex specific effect of ATPase inhibitory factor 1 on body weight: studies in high fat diet induced obese mice and genetic association studies in humans.
Kwak SY, Chung I, Kang J … +14 more , Perakakis N, Yoo EH, Lee J, Jung HT, Mun BR, Choi WS, Kim OY, Kim S, Kim EK, Oh H, Mantzoros CS, Chung JH, Kim HS, Shin MJ
Metabolism · 2020 Apr · PMID 32006557 · Publisher ↗
BACKGROUND: Based on the metabolic effect of exogenous ATPase inhibitory factor 1 (IF1) on glucose metabolism, we tested whether IF1 treatment is effective in ameliorating weight gain and whether its effects are sex spec...
BACKGROUND: Based on the metabolic effect of exogenous ATPase inhibitory factor 1 (IF1) on glucose metabolism, we tested whether IF1 treatment is effective in ameliorating weight gain and whether its effects are sex specific. METHODS: HFD-fed C57BL/6 mice were treated with IF1 (5 mg/kg body weight, injected intraperitoneally). The underlying mechanisms of effect of IF1 on body weight were investigated in vitro and in vivo. Associations between genotypes of IF1 and obesity and relevant phenotype were further tested at the population level. RESULTS: Chronic treatment with IF1 significantly decreased body weight gain by regulating food intake of HFD-fed male mice. IF1 activated the AKT/mTORC pathway and modulated the expression of appetite genes in the hypothalamus of HFD-fed male mice and its effect was confirmed in hypothalamic cell lines as well as hypothalamic primary cells. This required the interaction of IF1 with β-F1-ATPase on the plasma membrane of hypothalamic cells, which led to an increase in extracellular ATP production. In addition, IF1 treatment showed sympathetic nerve activation as measured by serum norepinephrine levels and UCP-1 expression in the subcutaneous fat of HFD-fed male mice. Notably, administration of recombinant IF1 to HFD-fed ovariectomized female mice showed remarkable reductions in food intake as well as body weight, which was not observed in wild-type 5-week female mice. Lastly, sex-specific genotype associations of IF1 with obesity prevalence and metabolic traits were demonstrated at the population level in humans. IF1 genetic variant (rs3767303) was significantly associated with lower prevalence of obesity and lower levels of body mass index, waist circumference, hemoglobin A, and glucose response area only in male participants. CONCLUSION: IF1 is involved in weight regulation by controlling food intake and potentially sympathetic nerve activation in a sex-specific manner.
Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion.
Han X, Raun SH, Carlsson M … +11 more , Sjøberg KA, Henriquez-Olguín C, Ali M, Lundsgaard AM, Fritzen AM, Møller LLV, Li Z, Li J, Jensen TE, Kiens B, Sylow L
Metabolism · 2020 Apr · PMID 31987858 · Publisher ↗
BACKGROUND: Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The...
BACKGROUND: Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. METHODS: Glucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. RESULTS: LLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4 (+18%), AKT (+65%), and AKT (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. CONCLUSIONS: Cancer can result in marked perturbations on at least six metabolically essential functions; i) insulin's blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.
Metabolic flexibility is impaired in women who are pregnant and overweight/obese and related to insulin resistance and inflammation.
Tinius RA, Blankenship MM, Furgal KE … +6 more , Cade WT, Pearson KJ, Rowland NS, Pearson RC, Hoover DL, Maples JM
Metabolism · 2020 Mar · PMID 31930973 · Full text
CONTEXT: Maternal obesity is a significant public health concern that contributes to unfavorable outcomes such as inflammation and insulin resistance. Women with obesity may have impaired metabolic flexibility (i.e. an i...
CONTEXT: Maternal obesity is a significant public health concern that contributes to unfavorable outcomes such as inflammation and insulin resistance. Women with obesity may have impaired metabolic flexibility (i.e. an inability to adjust substrate metabolism according to fuel availability). Impaired metabolic flexibility during pregnancy may mediate poor pregnancy outcomes in women with obesity. PURPOSE: The purposes of this study were to: 1) compare metabolic flexibility between overweight/obese and lean women; and 2) determine the relationships between metabolic flexibility, inflammation following a high-fat meal, and maternal metabolic health outcomes (i.e. gestational weight gain and insulin resistance). PROCEDURES: This interventional physiology study assessed lipid oxidation rates via indirect calorimetry before and after consumption of a high-fat meal. The percent change in lipid metabolism was calculated to determine 'metabolic flexibility.' Maternal inflammatory profiles (CRP, IL-6, IL-8, IL-10, IL-12, TNF-α) and insulin resistance (HOMA-IR) were determined via plasma analyses. MAIN FINDINGS: 64 women who were pregnant (lean = 35, overweight/obese = 29) participated between 32 and 38 weeks gestation. Lean women had significantly higher metabolic flexibility compared to overweight/obese women (lean 48.0 ± 34.1% vs overweight/obese 29.3 ± 34.3%, p = .035). Even when controlling for pre-pregnancy BMI, there was a negative relationship between metabolic flexibility and percent change in CRP among the overweight/obese group (r = -0.526, p = .017). Metabolic flexibility (per kg fat free mass) was negatively correlated with postprandial HOMA-IR (2 h: r = -0.325, p = .016; 4 h: r = -0.319, p = .019). CONCLUSIONS: Overweight and obese women who are pregnant are less 'metabolically flexible' than lean women, and this is related to postprandial inflammation and insulin resistance.
The combination of linagliptin, metformin and lifestyle modification to prevent type 2 diabetes (PRELLIM). A randomized clinical trial.
Guardado-Mendoza R, Salazar-López SS, Álvarez-Canales M … +10 more , Farfán-Vázquez D, Martínez-López YE, Jiménez-Ceja LM, Suárez-Pérez EL, Angulo-Romero F, Evia-Viscarra ML, Montes de Oca-Loyola ML, Durán-Pérez EG, Folli F, Aguilar-García A
Metabolism · 2020 Mar · PMID 31887309 · Publisher ↗
BACKGROUND: Prediabetes is a highly prevalent health problem with a high risk of complications and progression to type 2 diabetes (T2D). The goals of this study were to evaluate the effect of the combination of lingalipt...
BACKGROUND: Prediabetes is a highly prevalent health problem with a high risk of complications and progression to type 2 diabetes (T2D). The goals of this study were to evaluate the effect of the combination of lingaliptin + metformin + lifestyle on glucose tolerance, pancreatic β-cell function and T2D incidence in patients with prediabetes. METHODS: A single center parallel double-blind randomized clinical trial with 24 months of follow-up in patients with impaired glucose tolerance plus two T2D risk factors which were randomized to linagliptin 5 mg + metformin 1700 mg daily + lifestyle (LM group) or metformin 1700 mg daily + lifestyle (M group). Primary outcomes were regression to normoglycemia and T2D incidence; glucose levels and pancreatic β-cell function were secondary outcomes. RESULTS: Subjects were screened for eligibility by OGTT and 144 patients with prediabetes were randomized to LM group (n = 74) or M group (n = 70); 52 and 36 participants in the LM group and 52 and 27 participants in the M group, completed the 12 and 24 months of treatment, respectively; average follow-up was 17 ± 6 and 18 ± 7 months in M and LM group, respectively. Glucose levels during OGTT improved more in LM group. OGTT disposition index (DI) improved significantly better during the first months in LM group, increasing from 1·31 (95% CI: 1·14-1·49) to 2·41 (95% CI: 2.10-2.72) and to 2.07 (95% CI: 1.82-2.31) at 6 and 24 months in LM group vs from 1.21 (95% CI: 0.98-1.34) to 1.56 (95% CI: 1.17-1.95) and to 1.72 (95% CI: 1.45-1.98) at 6 and 24 months in M group (p < .05). T2D incidence was higher in M group in comparison to LM group (HR 4.0, 95% CI: 1.24-13.04, p = .020). The probability of achieving normoglycemia was higher in LM group (OR 3.26 CI 95% 1.55-6.84). No major side effects were observed during the study. CONCLUSIONS: The combination of linagliptin, metformin and lifestyle improved significantly glucose metabolism and pancreatic β-cell function, and reduced T2D incidence in subjects with prediabetes as compared to metformin and lifestyle.
Serum endotoxin, gut permeability and skeletal muscle metabolic adaptations following a short term high fat diet in humans.
Bowser SM, McMillan RP, Boutagy NE … +7 more , Tarpey MD, Smithson AT, Osterberg KL, Neilson AP, Davy BM, Davy KP, Hulver MW
Metabolism · 2020 Feb · PMID 31785256 · Publisher ↗
BACKGROUND: Our previous work demonstrated that a short-term high fat diet (HFD) increased fasting serum endotoxin, altered postprandial excursions of serum endotoxin, and led to metabolic and transcriptional responses i...
BACKGROUND: Our previous work demonstrated that a short-term high fat diet (HFD) increased fasting serum endotoxin, altered postprandial excursions of serum endotoxin, and led to metabolic and transcriptional responses in skeletal muscle in young, healthy male humans. PURPOSE: The purpose of the present study was to determine if a short-term high fat diet: 1) increases intestinal permeability and, in turn, fasting endotoxin concentrations and 2) decreases postprandial skeletal muscle fat oxidation. METHODS: Thirteen normal weight young adult males (BMI 23.1 ± 0.8 kg/m, age 22.2 ± 0.4 years) were fed a control diet (55% carbohydrate, 30% fat, 9% of which was saturated, 15% protein) for two weeks, followed by 5 days of an isocaloric HFD (30% carbohydrate, 55% fat, 25% of which was saturated, 15% protein, isocaloric to the control diet). Intestinal permeability (via four sugar probe test) was assessed in the fasting state. Both before and after the HFD, a high fat meal challenge (HFM, 820 kcal, 25% carbohydrate, 63% fat, 26% of which was saturated, and 12% protein) was administered. After an overnight fast, blood samples were collected before and every hour for 4 h after the HFM to assess endotoxin, and other serum blood measures. Muscle biopsies were obtained from the vastus lateralis before and 4 h after the HFM in order to assess substrate oxidation (glucose, fatty acid and pyruvate) using radiolabeled techniques. Insulin sensitivity was assessed via intravenous glucose tolerance test. Intestinal permeability, blood samples and muscle biopsies were assessed in the same manner before and following the HFD. MAIN FINDINGS: Intestinal permeability was not affected by HFD (p > 0.05), but fasting endotoxin increased two fold following the HFD (p = 0.04). Glucose oxidation and fatty acid oxidation in skeletal muscle homogenates significantly increased after the HFM before the HFD (+97%, and +106% respectively) but declined after the HFM following 5 days of the HFD (-24% and +16% respectively). Fatty acid suppressibility of pyruvate oxidation increased significantly after the HFM (+32%) but this physiological effect was abolished following 5 days of the HFD (+7%). Insulin sensitivity did not change following the HFD. CONCLUSION: These findings demonstrate that in healthy young men, consuming an isocaloric HFD for 5 days increases fasting endotoxin, independent of changes in gut permeability. These changes in endotoxin are accompanied by a broad effect on skeletal muscle substrate metabolism including increases in postprandial fat oxidation. Importantly, the latter occurs independent of changes in body weight and whole-body insulin sensitivity.
The adiponectin receptor agonist AdipoRon normalizes glucose metabolism and prevents obesity but not growth retardation induced by glucocorticoids in young mice.
Nicolas S, Rochet N, Gautier N … +2 more , Chabry J, Pisani DF
Metabolism · 2020 Feb · PMID 31778708 · Publisher ↗
OBJECTIVE: Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disor...
OBJECTIVE: Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances. METHODS: 5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure. RESULTS: We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation. CONCLUSION: We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.
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