Publications by authors named "Samuel Klein"

257 Publications

Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility.

Endocrinology 2021 Mar;162(3)

Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri, USA.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.
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http://dx.doi.org/10.1210/endocr/bqab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853299PMC
March 2021

The Four Deadly Sins of Implicit Attitude Research.

Front Psychol 2020 18;11:604340. Epub 2021 Jan 18.

Department of Psychology, University of California, Davis, Davis, CA, United States.

In this article, we describe four theoretical and methodological problems that have impeded implicit attitude research and the popular understanding of its findings. The problems all revolve around assumptions made about the relationships among measures (indirect vs. versus direct), constructs (implicit vs. explicit attitudes), cognitive processes (e.g., associative vs. propositional), and features of processing (automatic vs. controlled). These assumptions have confused our understandings of exactly what we are measuring, the processes that produce implicit evaluations, the meaning of differences in implicit evaluations across people and contexts, the meaning of changes in implicit evaluations in response to intervention, and how implicit evaluations predict behavior. We describe formal modeling as one means to address these problems, and provide illustrative examples. Clarifying these issues has important implications for our understanding of who has particular implicit evaluations and why, when those evaluations are likely to be particularly problematic, how we might best try to change them, and what interventions are best suited to minimize the effects of implicit evaluations on behavior.
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http://dx.doi.org/10.3389/fpsyg.2020.604340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849589PMC
January 2021

Heterogeneity in insulin-stimulated glucose uptake among different muscle groups in healthy lean people and people with obesity.

Diabetologia 2021 Jan 29. Epub 2021 Jan 29.

Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA.

Aims/hypothesis: It has been proposed that muscle fibre type composition and perfusion are key determinants of insulin-stimulated muscle glucose uptake, and alterations in muscle fibre type composition and perfusion contribute to muscle, and consequently whole-body, insulin resistance in people with obesity. The goal of the study was to evaluate the relationships among muscle fibre type composition, perfusion and insulin-stimulated glucose uptake rates in healthy, lean people and people with obesity.

Methods: We measured insulin-stimulated whole-body glucose disposal and glucose uptake and perfusion rates in five major muscle groups (erector spinae, obliques, rectus abdominis, hamstrings, quadriceps) in 15 healthy lean people and 37 people with obesity by using the hyperinsulinaemic-euglycaemic clamp procedure in conjunction with [H]glucose tracer infusion (to assess whole-body glucose disposal) and positron emission tomography after injections of [O]HO (to assess muscle perfusion) and [F]fluorodeoxyglucose (to assess muscle glucose uptake). A biopsy from the vastus lateralis was obtained to assess fibre type composition.

Results: We found: (1) a twofold difference in glucose uptake rates among muscles in both the lean and obese groups (rectus abdominis: 67 [51, 78] and 32 [21, 55] μmol kg min in the lean and obese groups, respectively; erector spinae: 134 [103, 160] and 66 [24, 129] μmol kg min, respectively; median [IQR]) that was unrelated to perfusion or fibre type composition (assessed in the vastus only); (2) the impairment in insulin action in the obese compared with the lean group was not different among muscle groups; and (3) insulin-stimulated whole-body glucose disposal expressed per kg fat-free mass was linearly related with muscle glucose uptake rate (r = 0.65, p < 0.05).

Conclusions/interpretation: Obesity-associated insulin resistance is generalised across all major muscles, and is not caused by alterations in muscle fibre type composition or perfusion. In addition, insulin-stimulated whole-body glucose disposal relative to fat-free mass provides a reliable index of muscle glucose uptake rate.
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http://dx.doi.org/10.1007/s00125-021-05383-wDOI Listing
January 2021

Obesity and White Matter Neuroinflammation Related Edema in Alzheimer's Disease Dementia Biomarker Negative Cognitively Normal Individuals.

J Alzheimers Dis 2021 ;79(4):1801-1811

Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, USA.

Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood.

Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer's disease (AD) dementia.

Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N = 62) or overweight and obese (BMI ≥25, N = 42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL.

Results: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha = 0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers.

Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly.
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http://dx.doi.org/10.3233/JAD-201242DOI Listing
January 2021

Dynamic Shifts in the Composition of Resident and Recruited Macrophages Influence Tissue Remodeling in NASH.

Cell Rep 2021 Jan;34(2):108626

Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4 Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4 macrophages accumulate. In concert, monocyte-derived infiltrating macrophages enter the liver and consist of a transitional subset that expresses Cx3cr1/Ccr2 and a second subset characterized by expression of Trem2, Cd63, Cd9, and Gpmnb; markers ascribed to lipid-associated macrophages (LAMs). The Cx3cr1/Ccr2-expressing macrophages, referred to as C-LAMs, localize to macrophage aggregates and hepatic crown-like structures (hCLSs) in the steatotic liver. In C-motif chemokine receptor 2 (Ccr2)-deficient mice, C-LAMs fail to appear in the liver, and this prevents hCLS formation, reduces LAM numbers, and increases liver fibrosis. Taken together, our data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.
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http://dx.doi.org/10.1016/j.celrep.2020.108626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877246PMC
January 2021

Effect of Diet versus Gastric Bypass on Metabolic Function in Diabetes. Reply.

N Engl J Med 2020 12;383(24):2393-2394

Washington University School of Medicine, St. Louis, MO

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http://dx.doi.org/10.1056/NEJMc2030030DOI Listing
December 2020

Attenuated early pregnancy weight gain by prenatal lifestyle interventions does not prevent gestational diabetes in the LIFE-Moms consortium.

Diabetes Res Clin Pract 2021 Jan 22;171:108549. Epub 2020 Nov 22.

Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA.

Aims: To examine the effect of lifestyle (diet and physical activity) interventions on the prevalence of GDM, considering the method of GDM ascertainment and its association with early pregnancy characteristics and maternal and neonatal outcomes in the LIFE-Moms consortium.

Methods: LIFE-Moms evaluated the effects of lifestyle interventions to optimize gestational weight gain in 1148 pregnant women with BMI ≥ 25 kg/m and without known diabetes at enrollment, compared with standard care. GDM was assessed between 24 and 31-weeks gestation by a 2-hour, 75-gram OGTT or by local clinical practice standards.

Results: Lifestyle interventions initiated prior to 16 weeks reduced early excess GWG compared with standard care (0.35 ± 0.24 vs 0.43 ± 0.26 kg per week, p=<0.0001) but did not affect GDM diagnosis (11.1% vs 11.6%, p = 0.91). Using the 75-gram, 2-hour OGTT, 13. 0% of standard care and 11.0% of the intervention group had GDM by the IADPSG criteria (p = 0.45). The 'type of diagnostic test' did not change the result (p = 0.86). Women who developed GDM were significantly heavier, more likely to have obesity, and more likely to have dysglycemia at baseline.

Conclusion: Moderate-to-high intensity lifestyle interventions grounded in behavior change theory initiated between 9 and 16-weeks gestation did not affect the prevalence of GDM despite reducing early GWG. CLINICALTRIALS.GOV: NCT01545934, NCT01616147, NCT01771133, NCT01631747, NCT01768793, NCT01610752, NCT01812694.
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http://dx.doi.org/10.1016/j.diabres.2020.108549DOI Listing
January 2021

Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity.

J Clin Invest 2020 12;130(12):6688-6699

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, and.

BACKGROUNDData from studies conducted in rodent models have shown that decreased adipose tissue (AT) oxygenation is involved in the pathogenesis of obesity-induced insulin resistance. Here, we evaluated the potential influence of AT oxygenation on AT biology and insulin sensitivity in people.METHODSWe evaluated subcutaneous AT oxygen partial pressure (pO2); liver and whole-body insulin sensitivity; AT expression of genes and pathways involved in inflammation, fibrosis, and branched-chain amino acid (BCAA) catabolism; systemic markers of inflammation; and plasma BCAA concentrations, in 3 groups of participants that were rigorously stratified by adiposity and insulin sensitivity: metabolically healthy lean (MHL; n = 11), metabolically healthy obese (MHO; n = 15), and metabolically unhealthy obese (MUO; n = 20).RESULTSAT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with the expression of genes involved in BCAA catabolism, in conjunction with an inverse relationship between AT pO2 and plasma BCAA concentrations. AT pO2 was negatively associated with AT gene expression of markers of inflammation and fibrosis. Plasma PAI-1 increased from the MHL to the MHO to the MUO group and was negatively correlated with AT pO2, whereas the plasma concentrations of other cytokines and chemokines were not different among the MHL and MUO groups.CONCLUSIONThese results support the notion that reduced AT oxygenation in individuals with obesity contributes to insulin resistance by increasing plasma PAI-1 concentrations and decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants K01DK109119, T32HL130357, K01DK116917, R01ES027595, P42ES010337, DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK052574 (Digestive Disease Research Center), and UL1TR002345 (Clinical and Translational Science Award); NIH Shared Instrumentation Grants S10RR0227552, S10OD020025, and S10OD026929; and the Foundation for Barnes-Jewish Hospital.
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http://dx.doi.org/10.1172/JCI141828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685757PMC
December 2020

Neural anomalies during vigilance in schizophrenia: Diagnostic specificity and genetic associations.

Neuroimage Clin 2020 8;28:102414. Epub 2020 Sep 8.

Minneapolis Veterans Affairs Health Care System, 1 Veterans Dr. Minneapolis, MN 55417, USA; University of Minnesota, Department of Psychiatry and Behavioral Science, 606 24th Ave S, Minneapolis, MN 55454, USA. Electronic address:

Impaired vigilance is a core cognitive deficit in schizophrenia and may serve as an endophenotype (i.e., mark genetic liability). We used a continuous performance task with perceptually degraded stimuli in schizophrenia patients (N = 48), bipolar disorder patients (N = 26), first-degree biological relatives of schizophrenia patients (N = 55) and bipolar disorder patients (N = 28), as well as healthy controls (N = 68) to clarify whether previously reported vigilance deficits and abnormal neural functions were indicative of genetic liability for schizophrenia as opposed to a generalized liability for severe psychopathology. We also examined variation in the Catechol-O-methyltransferase gene to evaluate whether brain responses were related to genetic variation associated with higher-order cognition. Relatives of schizophrenia patients had an increased rate of misidentification of nontarget stimuli as targets when they were perceptually similar, suggestive of difficulties with contour perception. Larger early visual responses (i.e., N1) were associated with better task performance in patients with schizophrenia consistent with enhanced N1 responses reflecting beneficial neural compensation. Additionally, reduced N2 augmentation to target stimuli was specific to schizophrenia. Both patients with schizophrenia and first-degree relatives displayed reduced late cognitive responses (P3b) that predicted worse performance. First-degree relatives of bipolar patients exhibited performance deficits, and displayed aberrant neural responses that were milder than individuals with liability for schizophrenia and dependent on sex. Variation in the Catechol-O-methyltransferase gene was differentially associated with P3b in schizophrenia and bipolar groups. Poor vigilance in schizophrenia is specifically predicted by a failure to enhance early visual responses, weak augmentation of mid-latency brain responses to targets, and limited engagement of late cognitive responses that may be tied to genetic variation associated with prefrontal dopaminergic availability. Experimental results illustrate specific neural functions that distinguish schizophrenia from bipolar disorder and provides evidence for a putative endophenotype that differentiates genetic liability for schizophrenia from severe mental illness more broadly.
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http://dx.doi.org/10.1016/j.nicl.2020.102414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502576PMC
September 2020

Perceptual Mechanisms of Visual Hallucinations and Illusions in Psychosis.

J Psychiatr Brain Sci 2020 21;5. Epub 2020 Aug 21.

Minneapolis Veterans Affairs Health Care System, 1 Veterans Dr, Minneapolis, MN 55417, USA.

Psychosis has been associated with neural anomalies across a number of brain regions and cortical networks. Nevertheless, the exact pathophysiology of the disorder remains unclear. Aberrant visual perceptions such as hallucinations are evident in psychosis, while the occurrence of visual distortions is elevated in individuals with genetic liability for psychosis. The overall goals of this project are to: (1) use psychophysical tasks and neuroimaging to characterize deficits in visual perception; (2) acquire a mechanistic understanding of these deficits through development and validation of a computational model; and (3) determine if said mechanisms mark genetic liability for psychosis. Visual tasks tapping both low- and high-level visual processing are being completed as individuals with psychotic disorders (IPD), first-degree biological siblings of IPDs (SibIPDs) and healthy controls (HCs) undergo 248-channel magneto-encephalography (MEG) recordings followed by 7 Tesla functional magnetic resonance imaging (MRI). By deriving cortical source signals from MEG and MRI data, we will characterize the timing, location and coordination of neural processes. We hypothesize that IPDs prone to visual hallucinations will exhibit deviant functions within early visual cortex, and that aberrant contextual influences on visual perception will involve higher-level visual cortical regions and be associated with visual hallucinations. SibIPDs who experience visual distortions-but not hallucinations-are hypothesized to exhibit deficits in higher-order visual processing reflected in abnormal inter-regional neural synchronization. We hope the results lead to the development of targeted interventions for psychotic disorders, as well as identify useful biomarkers for aberrant neural functions that give rise to psychosis.
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http://dx.doi.org/10.20900/jpbs.20200020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494209PMC
August 2020

Effects of Diet versus Gastric Bypass on Metabolic Function in Diabetes.

N Engl J Med 2020 08;383(8):721-732

From the Center for Human Nutrition (M.Y., B.D.K., J.Y., R.I.S., D.R., K.S., B.W.P., S.K.) and the Department of Surgery (J.C.E., S.R.E.), Washington University School of Medicine, St. Louis; and the Departments of Medicine (J.D.W., M.J.), Pharmacology (J.D.W., M.J.), Pediatrics (R.K.), and Computer Science and Engineering (R.K.), University of California San Diego, San Diego.

Background: Some studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss.

Methods: We evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles.

Results: Weight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 μmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 μmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) μmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 μmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 μmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group.

Conclusions: In this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.).
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http://dx.doi.org/10.1056/NEJMoa2003697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456610PMC
August 2020

Estimation of the Adhesion Interface Performance in Aluminum-PLA Joints by Thermographic Monitoring of the Material Extrusion Process.

Materials (Basel) 2020 Jul 29;13(15). Epub 2020 Jul 29.

Chair for Lightweight Systems, Saarland University, Campus E3 1, 66123 Saarbrücken, Germany.

Using additive manufacturing to generate a polymer-metal structure offers the potential to achieve a complex customized polymer structure joined to a metal base of high stiffness and strength. A tool to evaluate the generated interface during the process is of fundamental interest, as the sequential deposition of the polymer as well as temperature gradients within the substrate lead to local variations in adhesion depending on the local processing conditions. On preheated aluminum substrates, 0.3 and 0.6 mm high traces of polylactic acid (PLA) were deposited. Based on differential scanning calorimetry (DSC) and rheometry measurements, the substrate temperature was varied in between 150 and 200 °C to identify an optimized manufacturing process. Decreasing the layer height and increasing the substrate temperature promoted wetting and improved the adhesion interface performance as measured in a single lap shear test (up to 7 MPa). Thermographic monitoring was conducted at an angle of 25° with respect to the substrate surface and allowed a thermal evaluation of the process at any position on the substrate. Based on the thermographic information acquired during the first second after extrusion and the preset shape of the polymer trace, the resulting wetting and shear strength were estimated.
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http://dx.doi.org/10.3390/ma13153371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435926PMC
July 2020

Obesity Is Associated With Increased Basal and Postprandial β-Cell Insulin Secretion Even in the Absence of Insulin Resistance.

Diabetes 2020 10 10;69(10):2112-2119. Epub 2020 Jul 10.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO

We tested the hypothesis that obesity, independent of insulin resistance, is associated with increased insulin secretion. We compared insulin kinetics before and after glucose ingestion in lean healthy people and people with obesity who were matched on multiorgan insulin sensitivity (inhibition of adipose tissue lipolysis and glucose production and stimulation of muscle glucose uptake) as assessed by using a two-stage hyperinsulinemic-euglycemic pancreatic clamp procedure in conjunction with glucose and palmitate tracer infusions and positron emission tomography. We also evaluated the effect of diet-induced weight loss on insulin secretion in people with obesity who did not improve insulin sensitivity despite marked (∼20%) weight loss. Basal and postprandial insulin secretion rates were >50% greater in people with obesity than lean people even though insulin sensitivity was not different between groups. Weight loss in people with obesity decreased insulin secretion by 35% even though insulin sensitivity did not change. These results demonstrate that increased insulin secretion in people with obesity is associated with excess adiposity itself and is not simply a compensatory response to insulin resistance. These findings have important implications regarding the pathogenesis of diabetes because hyperinsulinemia causes insulin resistance and insulin hypersecretion is an independent risk factor for developing diabetes.
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http://dx.doi.org/10.2337/db20-0377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506835PMC
October 2020

Lean Americans With Nonalcoholic Fatty Liver Disease Have Lower Rates of Cirrhosis and Comorbid Diseases.

Clin Gastroenterol Hepatol 2020 Jul 3. Epub 2020 Jul 3.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI).

Methods: We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study. A total of 3386 patients with NAFLD were enrolled from August 2016 through March 2019. The odds ratios of cirrhosis, CVD, and metabolic abnormalities were estimated by age and race, adjusting for sex and center type.

Results: Based on standard BMI cutoff values, 12.8% of study subjects were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean participants, and proportions decreased as BMI categories increased (P < .0001). Lower proportions of lean participants had cirrhosis (22.6% vs 40.2% of non-lean participants), CVD history (9.0% vs 14.8% of nonlean participants), diabetes (32.6% vs 53.5% of non-lean participants), hypertension (47.8% vs 67.4% of non-lean participants), or dyslipidemia (54.0% vs 64.1% of non-lean participants). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After we adjusted for age, sex, and center type and site, the odds of NAFLD-associated cirrhosis in Asians who were lean was almost half the odds of NAFLD-associated cirrhosis in non-Asians who were lean (odds ratio, 0.47; 95% CI, 0.29-0.77).

Conclusions: More than 10% participants in a cohort of persons with NAFLD in the United States are lean; Asians account for almost half of the lean persons with NAFLD. Lean participants had a lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-lean persons with NAFLD. Asian participants had a significantly lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-Asians in all BMI categories. ClinicalTrials.gov, Number: NCT02815891.
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http://dx.doi.org/10.1016/j.cgh.2020.06.066DOI Listing
July 2020

Effects of Norepinephrine, Propofol, and Hemoglobin Concentration on Dynamic Measurements of Cerebrovascular Reactivity in Acute Brain Injury.

J Neurotrauma 2021 Feb 10;38(4):506-512. Epub 2020 Aug 10.

Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium.

Effects of treatment-associated variables on cerebrovascular autoregulation (CA) in acute brain injury patients remain unclear. As deficient CA is associated with worse outcomes and ideas about CA-steered management are emerging, this question is relevant. We investigated effects of norepinephrine and propofol infusion rates and hemoglobin concentration on dynamic measurements of cerebrovascular reactivity as surrogate for CA. A retrospective analysis of 91 traumatic brain injury (TBI) and 13 stroke patients admitted to the intensive care unit (ICU) of the Leuven University Hospitals was performed. Low-resolution autoregulation index (LAx) and high-frequency pressure reactivity index (PRx) were calculated as measurements of cerebrovascular reactivity. Data was binned into 5-, 15-, and 60-min intervals. Bivariate time-series analysis using lagged cross-correlations were calculated after pre-whitening and differencing. Linear mixed models evaluated effects of age, gender, cardiovascular risk, brain comorbidity, Glasgow Coma Scale (GCS), pupil reactivity, and type of injury. Median dose of norepinephrine, propofol and hemoglobin concentration was 7.8 μg/kg/h (Q1 3.6-Q3 13.8), 3 mg/kg/h (Q1 1.9-Q3 4.3), and 9.2 g·dL (Q1 8.2-Q3 10.5), respectively. Mean cross-correlations for 24 lags were close to zero and not significant for all variables. No significant differences as function of age, gender, cardiovascular risk, brain comorbidity, GCS, pupil reactivity, and type of injury were found. Dynamic intracranial pressure-based measurements of cerebrovascular reactivity in acute brain injured patients are not affected by gradually adjusted norepinephrine or propofol infusion rates or slow changes in hemoglobin concentration within the typical ranges during ICU admission. Future trials on cerebrovascular reactivity-steered management and treatment of CA impairment may not have to take these variables into account.
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http://dx.doi.org/10.1089/neu.2020.7160DOI Listing
February 2021

Mindfulness, Education, and Exercise for age-related cognitive decline: Study protocol, pilot study results, and description of the baseline sample.

Clin Trials 2020 10 27;17(5):581-594. Epub 2020 Jun 27.

Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.

Background/aims: Age-related cognitive decline is a pervasive problem in our aging population. To date, no pharmacological treatments to halt or reverse cognitive decline are available. Behavioral interventions, such as physical exercise and Mindfulness-Based Stress Reduction, may reduce or reverse cognitive decline, but rigorously designed randomized controlled trials are needed to test the efficacy of such interventions.

Methods: Here, we describe the design of the Mindfulness, Education, and Exercise study, an 18-month randomized controlled trial that will assess the effect of two interventions-mindfulness training plus moderate-to-vigorous intensity exercise or moderate-to-vigorous intensity exercise alone-compared with a health education control group on cognitive function in older adults. An extensive battery of biobehavioral assessments will be used to understand the mechanisms of cognitive remediation, by using structural and resting state functional magnetic resonance imaging, insulin sensitivity, inflammation, and metabolic and behavioral assessments.

Results: We provide the results from a preliminary study (n = 29) of non-randomized pilot participants who received both the exercise and Mindfulness-Based Stress Reduction interventions. We also provide details on the recruitment and baseline characteristics of the randomized controlled trial sample (n = 585).

Conclusion: When complete, the Mindfulness, Education, and Exercise study will inform the research community on the efficacy of these widely available interventions improve cognitive functioning in older adults.
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http://dx.doi.org/10.1177/1740774520931864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529857PMC
October 2020

Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics.

J Clin Invest 2020 06;130(6):3305-3314

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.

BACKGROUNDInsulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear.METHODSA hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22).RESULTSInsulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear.CONCLUSIONHyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver's maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGNIH grants DK56341 (Nutrition Obesity Research Center), DK052574 (Digestive Disease Research Center), RR024992 (Clinical and Translational Science Award), and T32 DK007120 (a T32 Ruth L. Kirschstein National Research Service Award); the American Diabetes Foundation (1-18-ICTS-119); Janssen Research & Development; and the Pershing Square Foundation.
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http://dx.doi.org/10.1172/JCI136756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260030PMC
June 2020

Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction.

Sci Rep 2020 02 25;10(1):3417. Epub 2020 Feb 25.

Merck & Co., Inc., South San Francisco, CA, USA.

Insulin resistance increases patients' risk of developing type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and the germline Grb14-knockout (KO) mice have improved insulin signaling in liver and skeletal muscle. Here, we show that Grb14 knockdown in liver, white adipose tissues, and heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and impaired systolic function, which could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in cardiac function as measured by echocardiography in the Grb14-knockdown mice fed a high-fat diet for a period of four months. While additional studies are needed to further confirm the efficacy and to de-risk potential negative cardiac effects in preclinical models, our data support the therapeutic strategy of inhibiting Grb14 to treat diabetes and related conditions.
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http://dx.doi.org/10.1038/s41598-020-60290-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042267PMC
February 2020

Striatal Dopamine Responses to Feeding are Altered in People with Obesity.

Obesity (Silver Spring) 2020 04 21;28(4):765-771. Epub 2020 Feb 21.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.

Objective: This study determined whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted than in the fed state in people with obesity.

Methods: Striatal DA release was evaluated in 10 people with obesity and prediabetes after consuming a meal to satiation and after fasting overnight as well as in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight by using positron emission tomography with [ C]raclopride injection.

Results: Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (P < 0.05), but there was no difference in the magnitude of the response between fasting and fed conditions.

Conclusions: People with obesity and prediabetes do not increase striatal DA release after eating a meal to satiation compared with fasting overnight and fail to inhibit DA release in response to high-calorie food stimuli after eating a meal to satiation. These data suggest that impaired DA signaling contributes to greater energy intake during meals in this population.
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http://dx.doi.org/10.1002/oby.22753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093218PMC
April 2020

Emergence of negative affect as motivation for drug taking in rats chronically self-administering cocaine.

Psychopharmacology (Berl) 2020 May 3;237(5):1407-1420. Epub 2020 Feb 3.

Department of Psychology, Rutgers University, 152 Frelinghuysen Road, Piscataway, NJ, 08854, USA.

Rationale: The role of negative affect as a motivational factor in animal models of drug addiction has been underexplored in the context of cocaine self-administration.

Objectives: The present investigation studied the relationship between magnitude of affective response and quantity of cocaine consumed in order to clarify the affective components that drive drug use in a preclinical model.

Methods: Rats self-administered (SA) cocaine 6 h/day for 14 consecutive days while their ultrasonic vocalizations (USVs) were recorded.

Results: Animals displayed an increase in 50-kHz call rates (indicating positive affect) when their drug levels were rapidly rising and an increase in 22-kHz call rates (indicating negative affect) when forced to abstain. The rate of 50-kHz calls predicted drug consumption during the 1st week of SA, but not week two. Contrarily, there was a strongly predictive positive association between rate of 22-kHz calls and amount of drug consumed during the 2nd week of SA.

Conclusions: Experimental results indicate that after chronic cocaine self-administration, negative affect emerges when animals are deprived of expected drug during withdrawal. Moreover, the increase in USVs indicating negative affect when deprived of drug was directly related to drug intake, concurrent with a decay in the direct relationship between USVs indicating positive affect and drug intake. The present preclinical support for the widely hypothesized shift from positive to negative affect as a salient motivational factor in human drug abuse adds to growing evidence of the unique value of rat USVs for understanding the role of emotion in drug addiction.
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http://dx.doi.org/10.1007/s00213-020-05468-1DOI Listing
May 2020

Dysregulation of Amyloid Precursor Protein Impairs Adipose Tissue Mitochondrial Function and Promotes Obesity.

Nat Metab 2019 12 13;1(12):1243-1257. Epub 2019 Dec 13.

Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect in adipocyte biology. Here, we report a role for amyloid precursor protein (APP) in compromising WAT mitochondrial function through a high-fat diet (HFD)-induced, unconventional mis-localization to mitochondria that further promotes obesity. In humans and mice, obese conditions significantly induce APP production in WAT and its enrichment in mitochondria. Mechanistically, a HFD-induced dysregulation of signal recognition particle subunit 54c is responsible for the mis-targeting of APP to adipocyte mitochondria. Mis-localized APP blocks the protein import machinery, leading to mitochondrial dysfunction in WAT. Adipocyte-specific and mitochondria-targeted APP overexpressing mice display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT due to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with significant protection from weight gain and systemic metabolic deficiency. Our data highlights an important role of APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction.
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http://dx.doi.org/10.1038/s42255-019-0149-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980705PMC
December 2019

Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease.

J Clin Invest 2020 03;130(3):1453-1460

Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.
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http://dx.doi.org/10.1172/JCI134165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269561PMC
March 2020

The Bedside Ice Pack Test for Myasthenia Gravis.

J Emerg Med 2020 Feb 30;58(2):334-335. Epub 2019 Nov 30.

Department of Emergency Medicine, Cook County Health and Hospitals System, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.jemermed.2019.10.020DOI Listing
February 2020

A word of caution against excessive protein intake.

Nat Rev Endocrinol 2020 01 14;16(1):59-66. Epub 2019 Nov 14.

Center for Human Nutrition, Washington University School of Medicine, St Louis, MO, USA.

Dietary protein is crucial for human health because it provides essential amino acids for protein synthesis. In addition, dietary protein is more satiating than carbohydrate and fat. Accordingly, many people consider the protein content when purchasing food and beverages and report 'trying to eat more protein'. The global market for protein ingredients is projected to reach approximately US$90 billion by 2021, largely driven by the growing demand for protein-fortified food products. This Perspective serves as a caution against the trend of protein-enriched diets and provides an evidence-based counterpoint that underscores the potential adverse public health consequences of high protein intake.
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http://dx.doi.org/10.1038/s41574-019-0274-7DOI Listing
January 2020

Adipose tissue NAD biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

Proc Natl Acad Sci U S A 2019 11 6;116(47):23822-23828. Epub 2019 Nov 6.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO 63110;

Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase () knockout (ANKO) and brown adipocyte-specific knockout (BANKO) mice because NAMPT is the rate-limiting NAD biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.
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http://dx.doi.org/10.1073/pnas.1909917116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876243PMC
November 2019

Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass.

Cell Metab 2019 11 3;30(5):855-864.e3. Epub 2019 Oct 3.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA; Departments of Medicine and Pharmacology, University of California, San Diego, San Diego, CA, USA. Electronic address:

Diabetes remission is greater after biliopancreatic diversion (BPD) than Roux-en-Y gastric bypass (RYGB) surgery. We used a mixed-meal test with ingested and infused glucose tracers and the hyperinsulinemic-euglycemic clamp procedure with glucose tracer infusion to assess the effect of 20% weight loss induced by either RYGB or BPD on glucoregulation in people with obesity (ClinicalTrials.gov number: NCT03111953). The rate of appearance of ingested glucose into the circulation was much slower, and the postprandial increases in plasma glucose and insulin concentrations were markedly blunted after BPD compared to after RYGB. Insulin sensitivity, assessed as glucose disposal rate during insulin infusion, was ∼45% greater after BPD than RYGB, whereas β cell function was not different between groups. These results demonstrate that compared with matched-percentage weight loss induced by RYGB, BPD has unique beneficial effects on glycemic control, manifested by slower postprandial glucose absorption, blunted postprandial plasma glucose and insulin excursions, and greater improvement in insulin sensitivity.
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http://dx.doi.org/10.1016/j.cmet.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876863PMC
November 2019

Knockdown of Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity.

Nat Metab 2019 01 19;1(1):86-97. Epub 2018 Nov 19.

Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA 92093, USA.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.
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http://dx.doi.org/10.1038/s42255-018-0003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746433PMC
January 2019

Metabolically healthy obesity: facts and fantasies.

J Clin Invest 2019 10;129(10):3978-3989

Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered "metabolically healthy." However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO - specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.
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http://dx.doi.org/10.1172/JCI129186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763224PMC
October 2019

Obesity dysregulates fasting-induced changes in glucagon secretion.

J Endocrinol 2019 11;243(2):149-160

Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Hyperglucagonemia, a hallmark in obesity and insulin resistance promotes hepatic glucose output, exacerbating hyperglycemia and thus predisposing to the development type 2 diabetes. As such, glucagon signaling is a key target for new therapeutics to manage insulin resistance. We evaluated glucagon homeostasis in lean and obese mice and people. In lean mice, fasting for 24 h caused a rise in glucagon. In contrast, a decrease in serum glucagon compared to baseline was observed in diet-induced obese mice between 8 and 24 h of fasting. Fasting decreased serum insulin in both lean and obese mice. Accordingly, the glucagon:insulin ratio was unaffected by fasting in obese mice but increased in lean mice. Re-feeding (2 h) restored hyperglucagonemia in obese mice. Pancreatic perfusion studies confirm that fasting (16 h) decreases pancreatic glucagon secretion in obese mice. Consistent with our findings in the mouse, a mixed meal increased serum glucagon and insulin concentrations in obese humans, both of which decreased with time after a meal. Consequently, fasting and re-feeding less robustly affected glucagon:insulin ratios in obese compared to lean participants. The glucoregulatory disturbance in obesity may be driven by inappropriate regulation of glucagon by fasting and a static glucagon:insulin ratio.
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http://dx.doi.org/10.1530/JOE-19-0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994388PMC
November 2019

One-year postpartum anthropometric outcomes in mothers and children in the LIFE-Moms lifestyle intervention clinical trials.

Int J Obes (Lond) 2020 01 10;44(1):57-68. Epub 2019 Jul 10.

New York Obesity Research Center, Dept. of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Background/objectives: Excess gestational weight gain (GWG) is a risk factor for maternal postpartum weight retention and excessive neonatal adiposity, especially in women with overweight or obesity. Whether lifestyle interventions to reduce excess GWG also reduce 12-month maternal postpartum weight retention and infant weight-for-length z score is unknown. Randomized controlled trials from the LIFE-Moms consortium investigated lifestyle interventions that began in pregnancy and tested whether there was benefit through 12 months on maternal postpartum weight retention (i.e., the difference in weight from early pregnancy to 12 months) and infant-weight-for-length z scores.

Subjects/methods: In LIFE-Moms, women (N = 1150; 14.1 weeks gestation at enrollment) with overweight or obesity were randomized within each of seven trials to lifestyle intervention or standard care. Individual participant data were combined and analyzed using generalized linear mixed models with trial entered as a random effect. The 12-month assessment was completed by 83% (959/1150) of women and 84% (961/1150) of infants.

Results: Compared with standard care, lifestyle intervention reduced postpartum weight retention (2.2 ± 7.0 vs. 0.7 ± 6.2 kg, respectively; difference of -1.6 kg (95% CI -2.5, -0.7; p = 0.0003); the intervention effect was mediated by reduction in excess GWG, which explained 22% of the effect on postpartum weight retention. Lifestyle intervention also significantly increased the odds (OR = 1.68 (95% CI, 1.26, 2.24)) and percentage of mothers (48.2% vs. 36.2%) at or below baseline weight at 12 months postpartum (yes/no) compared with standard care. There was no statistically significant treatment group effect on infant anthropometric outcomes at 12 months.

Conclusions: Compared with standard care, lifestyle interventions initiated in pregnancy and focused on healthy eating, increased physical activity, and other behavioral strategies resulted in significantly less weight retention but similar infant anthropometric outcomes at 12 months postpartum in a large, diverse US population of women with overweight and obesity.
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http://dx.doi.org/10.1038/s41366-019-0410-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923171PMC
January 2020