Identifying pathways to early‐onset metabolic dysfunction, insulin resistance and inflammation in young adult inpatients with emerging affective and major mood disorders

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

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Insulin Resistance Is an Independent Determinate of ED in Young Adult Men

PLoS ONE ◽

10.1371/journal.pone.0083951 ◽

2013 ◽

Vol 8 (12) ◽

pp. e83951 ◽

Cited By ~ 12

Author(s):

Shengfu Chen ◽

Rongpei Wu ◽

Yanping Huang ◽

Fufu Zheng ◽

Yangbin Ou ◽

...

Keyword(s):

Insulin Resistance ◽

Young Adult ◽

Adult Men

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Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00401.2014 ◽

2015 ◽

Vol 308 (6) ◽

pp. R530-R542 ◽

Cited By ~ 34

Author(s):

Victoria J. Vieira-Potter ◽

Jaume Padilla ◽

Young-Min Park ◽

Rebecca J. Welly ◽

Rebecca J. Scroggins ◽

...

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Energy Expenditure ◽

Aerobic Fitness ◽

Resting Energy Expenditure ◽

Female Rats ◽

Metabolic Dysfunction ◽

Spontaneous Physical Activity ◽

Resting Energy

Ovariectomized rodents model human menopause in that they rapidly gain weight, reduce spontaneous physical activity (SPA), and develop metabolic dysfunction, including insulin resistance. How contrasting aerobic fitness levels impacts ovariectomy (OVX)-associated metabolic dysfunction is not known. Female rats selectively bred for high and low intrinsic aerobic fitness [high-capacity runners (HCR) and low-capacity runners (LCR), respectively] were maintained under sedentary conditions for 39 wk. Midway through the observation period, OVX or sham (SHM) operations were performed providing HCR-SHM, HCR-OVX, LCR-SHM, and LCR-OVX groups. Glucose tolerance, energy expenditure, and SPA were measured before and 4 wk after surgery, while body composition via dual-energy X-ray absorptiometry and adipose tissue distribution, brown adipose tissue (BAT), and skeletal muscle phenotype, hepatic lipid content, insulin resistance via homeostatic assessment model of insulin resistance and AdipoIR, and blood lipids were assessed at death. Remarkably, HCR were protected from OVX-associated increases in adiposity and insulin resistance, observed only in LCR. HCR rats were ∼30% smaller, had ∼70% greater spontaneous physical activity (SPA), consumed ∼10% more relative energy, had greater skeletal muscle proliferator-activated receptor coactivator 1-alpha, and ∼40% more BAT. OVX did not increase energy intake and reduced SPA to the same extent in both HCR and LCR. LCR were particularly affected by an OVX-associated reduction in resting energy expenditure and experienced a reduction in relative BAT; resting energy expenditure correlated positively with BAT across all animals ( r = 0.6; P < 0.001). In conclusion, despite reduced SPA following OVX, high intrinsic aerobic fitness protects against OVX-associated increases in adiposity and insulin resistance. The mechanism may involve preservation of resting energy expenditure.

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Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0032 ◽

2013 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Charmaine S. Tam ◽

Leanne M. Redman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Low Grade ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Proinflammatory Mediators ◽

Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

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Etiology and genetics of early-onset mood disorders

Child and Adolescent Psychiatric Clinics of North America ◽

10.1016/s1056-4993(02)00013-5 ◽

2002 ◽

Vol 11 (3) ◽

pp. 499-518 ◽

Cited By ~ 20

Author(s):

R TODD

Keyword(s):

Mood Disorders ◽

Early Onset

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Female offspring born to obese and insulin-resistant dams are not at increased risk for obesity and metabolic dysfunction during early development

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0371 ◽

2018 ◽

Vol 96 (1) ◽

pp. 97-102 ◽

Cited By ~ 1

Author(s):

Hanin Aburasayn ◽

Rami Al Batran ◽

Keshav Gopal ◽

Malak Almutairi ◽

Amina Eshreif ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Female Offspring ◽

Metabolic Dysfunction ◽

Insulin Resistant ◽

The Metabolic Syndrome ◽

Rate Versus ◽

Increased Risk ◽

Study Completion ◽

Reduced Rate

The percentage of women who are obese at the time of conception or during pregnancy is increasing, with animal and human studies demonstrating that offspring born to obese dams or mothers are at increased risk for obesity and the metabolic syndrome. Our goal was to confirm in an experimental model of metabolic syndrome in the dam, whether the offspring would be at increased risk of obesity. Conversely, we observed that male offspring born to dams with metabolic syndrome had no alterations in their body mass profiles, whereas female offspring born to dams with metabolic syndrome were heavier at weaning, but exhibited no perturbations in energy metabolism. Moreover, they gained weight at a reduced rate versus female offspring born to healthy dams, and thus weighed less at study completion. Hence, our findings suggest that factors other than increased adiposity and insulin resistance during pregnancy are responsible for the increased risk of obesity in children born to obese mothers.

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Prenatal alcohol exposure programs offspring disease: Insulin resistance in adult males in a rat model of acute exposure

10.1101/684639 ◽

2019 ◽

Author(s):

Tam M T Nguyen ◽

Sarah E Steane ◽

Karen M Moritz ◽

Lisa K Akison

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Chronic Disease ◽

Alcohol Consumption ◽

Fetal Development ◽

Prenatal Alcohol Exposure ◽

Alcohol Exposure ◽

Metabolic Dysfunction ◽

Specific Manner ◽

Prenatal Alcohol

AbstractAlcohol consumption is highly prevalent amongst women of reproductive age. Given that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect fetal development and program chronic disease in offspring. We examined the effect of an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague-Dawley rats received an oral gavage of ethanol (1g/kg maternal body weight, n=9 dams) or an equivalent volume of saline (control, n=8 dams) at embryonic days 13.5 and 14.5. PAE resulted in a blood alcohol concentration of 0.05-0.06% 1h post-gavage in dams. Fasting blood glucose concentration was not affected by PAE in offspring at any age, nor were blood glucose levels during a glucose tolerance test (GTT) in 6-month old offspring (P>0.5). However, there was evidence of insulin resistance in PAE male offspring at 6 months of age, with significantly elevated fasting plasma insulin (P= 0.001), a tendency for increased first phase insulin secretion during the GTT and impaired glucose clearance following an insulin challenge (P= 0.007). This was accompanied by modest alterations in protein kinase B (AKT) signalling in adipose tissue. PAE also resulted in reduced calorie consumption by offspring compared to controls (P= 0.04). These data suggest that a relatively low-level, acute PAE programs metabolic dysfunction in offspring in a sex-specific manner. These results highlight that alcohol consumption during pregnancy has the potential to affect the long-term health of offspring.Key points summaryPrenatal alcohol exposure has the potential to affect fetal development and program chronic disease in offspring.Previous preclinical models typically use high, chronic doses of alcohol throughout pregnancy to examine effects on offspring, particularly on the brain and behaviour.In this study we use a rat model of moderate, acute, prenatal alcohol exposure to determine if this can be detrimental to maintenance of glucose homeostasis in adolescent and adult offspring.Although female offspring were relatively unaffected, there was evidence of insulin resistance in 6-month old male offspring exposed to prenatal alcohol, suggestive of a pre-diabetic state.This result suggests that even a relatively low-dose, acute exposure to alcohol during pregnancy can still program metabolic dysfunction in a sex-specific manner.

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Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms222111629 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11629

Author(s):

Jorge Gutiérrez-Cuevas ◽

Arturo Santos ◽

Juan Armendariz-Borunda

Keyword(s):

Insulin Resistance ◽

Metabolic Disorders ◽

Molecular Mechanisms ◽

Causes Of Death ◽

Cardiovascular Prevention ◽

Atherogenic Dyslipidemia ◽

Metabolic Dysfunction ◽

Systemic Insulin Resistance ◽

Underlying Mechanisms

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.

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Evaluation of Peripheral Blood Neutrophil Functions after an Oral Carbohydrate Overload in Obese and Insulin Resistant Horses

10.21203/rs.3.rs-90317/v1 ◽

2020 ◽

Author(s):

Constanza Salinas ◽

Gabriel Espinosa ◽

Natalia Morales ◽

Claudio Henriquez ◽

Gabriel Moran ◽

...

Keyword(s):

Insulin Resistance ◽

Oxidative Burst ◽

Peripheral Blood ◽

Oral Glucose ◽

Close Monitoring ◽

Metabolic Dysfunction ◽

Phagocytic Capacity ◽

Insulin Resistant ◽

Peripheral Blood Neutrophil ◽

Stimulation Of

Abstract Background: Obesity and insulin resistance (IR) are conditions of increasing prevalence in populations of equids worldwide. The immune impairment described in metabolic dysfunction status in humans has been extensively reported with minimal data regarding horses. The objective of the study was to evaluate the effect of obesity as an isolated factor and in association with insulin resistance on apoptosis, phagocytosis and oxidative burst activity of neutrophils isolated from peripheral blood of lean and obese adult horses with or without insulin resistance, basally and after induction of hyperglycemia through an oral glucose test. Results: No differences in apoptosis were observed between experimental groups at any time point. Phagocytic capacity was significantly diminished at baseline in the obese-IR group (P<0.05) but increased after stimulation of hyperglycemia (P=0.007). Basal reactive oxygen species production differed significantly (P=0.0001) between the obese-insulin sensitive (IS) and lean-IS or obese-IR groups, and decreased significantly after stimulation of hyperglycemia in the lean-IS and obese-IS groups (P<0.05).Conclusions: Results from this study showed that both metabolic status itself, and acute hyperglycemia, are factors that influence PMNs functionality in horses, specifically phagocytosis and oxidative burst. This indicates the need for close monitoring of immune function in horses with inflammatory disease and concurrent obesity and insulin resistance.

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