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Diabetes Sep 2023In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found...
UNLABELLED
In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found that ablation of Gnas, the gene that encodes Gαs, in CD11c expressing cells protects mice from obesity, glucose intolerance, and insulin resistance. Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived cells and did not require adaptive immunity. Loss of cAMP signaling was associated with increased adipose tissue norepinephrine and cAMP signaling, and prevention of catecholamine resistance. The adipose tissue had reduced expression of catecholamine transport and degradation enzymes, suggesting that the elevated norepinephrine resulted from decreased catabolism. Collectively, our results identified an important role for cAMP signaling in CD11c+ innate immune cells in whole-body metabolism by controlling norepinephrine levels in white adipose tissue, modulating catecholamine-induced lipolysis and increasing thermogenesis, which, together, created a lean phenotype.
ARTICLE HIGHLIGHTS
We undertook this study to understand how immune cells communicate with adipocytes, specifically, whether cAMP signaling in the immune cell and the adipocyte are connected. We identified a reciprocal interaction between CD11c+ innate immune cells and adipocytes in which high cAMP signaling in the immune cell compartment induces low cAMP signaling in adipocytes and vice versa. This interaction regulates lipolysis in adipocytes and inflammation in immune cells, resulting in either a lean, obesity-resistant, and insulin-sensitive phenotype, or an obese, insulin-resistant phenotype.
Topics: Animals; Mice; Adipose Tissue, White; Catecholamines; Diet, High-Fat; Insulin; Insulin Resistance; Mice, Inbred C57BL; Norepinephrine; Obesity
PubMed: 37257047
DOI: 10.2337/db22-1035 -
The American Journal of Forensic... Dec 2023The PPA2 gene encodes a mitochondrial pyrophosphatase protein. Mutations in the gene are inherited in an autosomal recessive fashion and, when mutated, function to...
The PPA2 gene encodes a mitochondrial pyrophosphatase protein. Mutations in the gene are inherited in an autosomal recessive fashion and, when mutated, function to induce mitochondrial ATP production failure resulting in increased stress on the heart and sudden cardiac death, especially when combined with alcohol. Herein, we describe a case of a 19-year-old female patient with a history of "alcohol intolerance" who was found unexpectedly deceased after consuming a minimal amount of alcohol. Histological examination of her heart revealed widespread fibrosis of the left ventricle and the interventricular septum. Other findings include hypertrophied myocytes, including some with pleomorphic nuclei. Genetic studies were performed on postmortem blood, revealing heterozygous PPA2 gene mutations, the pathogenic variant c.683C>T (p.Pro228Leu), and the other variant c.814C>T (p.His272Tyr), a novel variant of undetermined significance. We propose that the variant of undetermined significance is likely a pathogenic mutation due to the decedent's phenotype.
Topics: Female; Humans; Adolescent; Young Adult; Adult; Mutation; Death, Sudden, Cardiac; Ethanol; Mitochondria; Fibrosis; Mitochondrial Proteins; Inorganic Pyrophosphatase
PubMed: 37249496
DOI: 10.1097/PAF.0000000000000841 -
American Journal of Physiology. Heart... Aug 2023Heart failure (HF) is a leading cause of morbidity and mortality particularly in older adults and patients with multiple metabolic comorbidities. Heart failure with...
Heart failure (HF) is a leading cause of morbidity and mortality particularly in older adults and patients with multiple metabolic comorbidities. Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with multisystem organ dysfunction in which patients develop symptoms of HF as a result of high left ventricular (LV) diastolic pressure in the context of normal or near normal LV ejection fraction (LVEF; ≥50%). Challenges to create and reproduce a robust rodent phenotype that recapitulates the multiple comorbidities that exist in this syndrome explain the presence of various animal models that fail to satisfy all the criteria of HFpEF. Using a continuous infusion of angiotensin II and phenylephrine (ANG II/PE), we demonstrate a strong HFpEF phenotype satisfying major clinically relevant manifestations and criteria of this pathology, including exercise intolerance, pulmonary edema, concentric myocardial hypertrophy, diastolic dysfunction, histological signs of microvascular impairment, and fibrosis. Conventional echocardiographic analysis of diastolic dysfunction identified early stages of HFpEF development and speckle tracking echocardiography analysis including the left atrium (LA) identified strain abnormalities indicative of contraction-relaxation cycle impairment. Diastolic dysfunction was validated by retrograde cardiac catheterization and analysis of LV end-diastolic pressure (LVEDP). Among mice that developed HFpEF, two major subgroups were identified with predominantly perivascular fibrosis and interstitial myocardial fibrosis. In addition to major phenotypic criteria of HFpEF that were evident at early stages of this model (3 and 10 days), accompanying RNAseq data demonstrate activation of pathways associated with myocardial metabolic changes, inflammation, activation of extracellular matrix (ECM) deposition, microvascular rarefaction, and pressure- and volume-related myocardial stress. Heart failure with preserved ejection fraction (HFpEF) is an emerging epidemic affecting up to half of patients with heart failure. Here we used a chronic angiotensin II/phenylephrine (ANG II/PE) infusion model and instituted an updated algorithm for HFpEF assessment. Given the simplicity in generating this model, it may become a useful tool for investigating pathogenic mechanisms, identification of diagnostic markers, and for drug discovery aimed at both prevention and treatment of HFpEF.
Topics: Animals; Mice; Heart Failure; Stroke Volume; Angiotensin II; Ventricular Function, Left; Cardiomyopathies; Disease Models, Animal; Fibrosis; Phenylephrine
PubMed: 37204871
DOI: 10.1152/ajpheart.00038.2023 -
Clinical Transplantation Sep 2023Kidney transplant (KT) recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes serum uric acid (sUA), and...
INTRODUCTION
Kidney transplant (KT) recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes serum uric acid (sUA), and its efficacy is not impacted by kidney function.
METHODS
This open-label, Phase 4 trial (PROTECT NCT04087720) examined safety and efficacy of pegloticase in 20 participants with KT > 1 year prior to enrollment and with uncontrolled gout (sUA ≥7 mg/dL, intolerance/inefficacy to urate lowering therapy, and ≥1 of the following: tophi, chronic gouty arthritis, ≥2 flares in past year) and functioning KT (estimated glomerular filtration rate [eGFR] ≥15 mL/min/1.73 m ) on stable immunosuppression therapy.
RESULTS
The primary endpoint was sUA response during month 6 (sUA < 6 mg/dL for ≥80% of time). The study enrolled 20 participants (mean ± SD); age: 53.9 ± 10.9 years, time since KT: 14.7 ± 6.9 years, sUA: 9.4 ± 1.5 mg/dL, gout duration: 8.4 ± 11.6 years; all on ≥2 stable doses of immunosuppression agents. Pegloticase (8 mg intravenous every 2 weeks) in KT recipients with uncontrolled gout showed a high response rate of 89% (16/18 responders). Two participants discontinued treatment solely due to COVID-19 concerns prior to month 6 were not included in the primary analysis. Pegloticase exposures were higher than those historically observed with pegloticase monotherapy, and no anaphylaxis or infusion reaction events occurred during the study.
CONCLUSIONS
This improved response rate to pegloticase in the KT population reflects observations from other trials and reports on immunomodulation with pegloticase. As the KT population has a high prevalence of gout and limitations with oral urate lowering medication options, these findings suggest a potential option for uncontrolled gout therapy in KT participants.
Topics: Adult; Humans; Middle Aged; COVID-19; Gout; Gout Suppressants; Kidney Transplantation; Polyethylene Glycols; Treatment Outcome; Uric Acid
PubMed: 37138473
DOI: 10.1111/ctr.14993 -
Social Psychiatry and Psychiatric... Oct 2023The self-medication hypothesis suggests people may develop Alcohol Use Disorder (AUD) or Non-Alcohol Substance Use Disorder (NA-SUD) following PTSD as a maladaptive way...
PURPOSE
The self-medication hypothesis suggests people may develop Alcohol Use Disorder (AUD) or Non-Alcohol Substance Use Disorder (NA-SUD) following PTSD as a maladaptive way of coping with PTSD symptoms. Given that an accumulation of trauma experiences and interpersonal trauma increase the likelihood and severity of PTSD, we sought to determine whether the number and type of traumas additionally predict AUD and NA-SUD following PTSD.
METHODS
We analysed data from 36,309 adult participants in the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) study (M = 45.63 years, SD = 17.53, 56.3% female) who were administered semi-structured diagnostic interviews of trauma exposure and PTSD, AUD and NA-SUD symptoms.
RESULTS
Individuals with PTSD were more likely to have an AUD or NA-SUD than those without PTSD. Endorsement of a greater number of traumas was associated with greater odds of having PTSD, AUD, or NA-SUD. Experience of interpersonal trauma was related to greater odds of having PTSD and subsequent AUD or NA-SUD than not experiencing interpersonal trauma. Multiple experiences of interpersonal trauma compared to one interpersonal trauma exposure also increased the odds of having PTSD followed by AUD or NA-SUD.
CONCLUSIONS
Interpersonal trauma and multiple experiences of interpersonal trauma may result in individuals turning to alcohol and substances as a way to alleviate intolerable PTSD symptomology, aligning with the self-medication hypothesis. Our findings highlight the importance of ensuring services and support for interpersonal trauma survivors and for those who have experienced multiple traumas given their increased for unfavourable outcomes.
Topics: Adult; Humans; Female; Male; Stress Disorders, Post-Traumatic; Substance-Related Disorders; Alcohol-Related Disorders; Alcoholism; Alcohol Drinking
PubMed: 37133523
DOI: 10.1007/s00127-023-02472-6 -
Journal of Interpersonal Violence Sep 2023Technology-facilitated intimate partner violence (T-IPV), including social media surveillance (SMS) and cyber dating abuse (CDA), are increasingly common post-breakup...
Technology-facilitated intimate partner violence (T-IPV), including social media surveillance (SMS) and cyber dating abuse (CDA), are increasingly common post-breakup experiences among college students. Although a large body of research has focused on identifying risk factors for both types of T-IPV, perpetrators of T-IPV may differ in their pattern of risk factors. Using the I model as a guiding framework, the current study sought to identify typologies of college students engaging in post-breakup SMS and CDA. Specifically, 710 college students' responses on self-report measures were examined for similarities in known risk factors, namely attachment anxiety, impulse control difficulties, lack of emotion regulation strategies, intolerance of uncertainty, distress tolerance, and problematic alcohol use. Three distinct perpetrator profiles emerged with attachment anxiety, alcohol use, and intolerance of uncertainty presenting as distinguishing features. Problematic alcohol use was evident in the moderate and high levels of SMS and CDA perpetration profiles. Contrary to what was expected, there appeared to be little variability in emotional regulation and impulse control abilities across the three profiles such that individuals belonging to low and high perpetration profiles did not differ in the degree to which they were able to control their impulses or access emotion regulation strategies. Results highlight the potential importance of tailoring interventions, while reducing transdiagnostic risk factors, to account for the heterogeneity in risk factors among T-IPV perpetrators.
Topics: Humans; Intimate Partner Violence; Risk Factors; Alcohol Drinking; Self Report; Students
PubMed: 37118945
DOI: 10.1177/08862605231171416 -
The British Journal of Nutrition Nov 2023Fasting is related to glucose intolerance and insulin resistance, but it is unknown whether the duration of fasting influences these factors. We explored whether... (Randomized Controlled Trial)
Randomized Controlled Trial
Fasting is related to glucose intolerance and insulin resistance, but it is unknown whether the duration of fasting influences these factors. We explored whether prolonged fasting increases norepinephrine and ketone concentrations and decreases core temperature to a greater extent than short-term fasting; if so, this should lead to improved glucose tolerance. Forty-three healthy young adult males were randomly assigned to undergo a 2-d fast, 6-d fast or the usual diet. Changes in rectal temperature (T, ketone and catecholamine concentrations, glucose tolerance and insulin release in response to an oral glucose tolerance test were assessed. Both fasting trials increased ketone concentration, and the effect was larger after the 6-d fast ( < 0·05). T and epinephrine concentration increased only after the 2-d fast ( < 0·05). Both fasting trials increased the glucose area under the curve (AUC) ( < 0·05), but the AUC remained higher than the baseline value after participants returned to their usual diet in the 2-d fast group ( < 0·05). Neither fasting had an immediate effect on the insulin AUC, although it increased after return to their usual diet in the 6-d fast group ( < 0·05). These data suggest that the 2-d fast elicited residual impaired glucose tolerance, which may be linked to greater perceived stress during short-term fasting, as shown by the epinephrine response and change in core temperature. By contrast, prolonged fasting seemed to evoke an adaptive residual mechanism that is related to improved insulin release and maintained glucose tolerance.
Topics: Male; Young Adult; Humans; Insulin; Blood Glucose; Glucose; Insulin Resistance; Glucose Intolerance; Intermittent Fasting; Epinephrine; Ketones; Fasting
PubMed: 36866742
DOI: 10.1017/S0007114523000557