Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

Chen, Weiyi; Balland, Eglantine; Cowley, Michael A.

doi:10.1159/000455865

Cited by 77 publications

(70 citation statements)

References 233 publications

(279 reference statements)

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“…Cortisol binds to receptors found in the peripheral and central nervous system, where its objective is to mobilize and redistribute energy stores to maintain homeostasis and minimize incurred damage to the individual until the threatening stimulus has passed [78]. Outcomes of chronic HPA-axis activation include effects on gluconeogenesis and glycogenolysis [79], lipolysis [80], insulin resistance [81,82], and compromised reproductive functions [83].…”

Section: Physiological Stressmentioning

confidence: 99%

Adolescent Obesity: Diet Quality, Psychosocial Health, and Cardiometabolic Risk Factors

et al. 2019

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Obesity is a multifaceted chronic condition with several contributing causes, including biological risk factors, socioeconomic status, health literacy, and numerous environmental influences. Of particular concern are the increasing rates of obesity in children and adolescents, as rates of obesity in youth in the United States have tripled within the last three decades. Youth from historically disadvantaged backgrounds tend to have higher rates of obesity compared to other groups. Adolescents often do not meet intake recommendations for certain food groups and nutrients, which may contribute to a heightened risk of obesity. With obesity disproportionately affecting adolescents (ages 12-19 years), negative effects of excess adiposity may be particularly salient during this critical period of development. The presentation of chronic cardiometabolic disease symptoms typically observed in adults, such as hypertension, hyperglycemia, dyslipidemia, and inflammation, are becoming increasingly common in adolescents with obesity. Additionally, there is dynamic interplay between obesity and psychosocial health, as adolescents with obesity may have increased levels of stress, depressive symptoms, and reduced resilience. To reduce and prevent adolescent obesity, the implementation of theory-driven multicomponent school-and community-based interventions have been suggested. These interventions promote knowledge and self-efficacy for healthful practices that have the potential to progress to sustained behavior change.

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Section: Physiological Stressmentioning

confidence: 99%

Adolescent Obesity: Diet Quality, Psychosocial Health, and Cardiometabolic Risk Factors

et al. 2019

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“…Diabetes mellitus was one of the first pathologies correlated with lipotoxicity [157,158] . In fact, the term lipotoxicity was coined after a seminal study where free fatty acids were associated with β-cell abnormalities such as lack of glucose-stimulated insulin secretion, decreased expression of GLUT2, and a rise in islet triacylglycerol content [159] .…”

Section: Hypothalamic Lipotoxicity and Er Stressmentioning

confidence: 99%

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

et al. 2016

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Hypothalamic lipid metabolism plays a major role in the physiological regulation of energy balance. Modulation of several enzymatic activities that control lipid biosynthesis, such as fatty acid synthase and AMP-activated protein kinase, impacts both feeding and energy expenditure. However, lipids can also cause pathological alterations in the hypothalamus. Lipotoxicity is promoted by excess lipids in tissues not suitable for their storage. A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases such as insulin resistance, cardiomyopathy, atherosclerosis, and steatohepatitis. Current data have reported that, similar to what is observed in peripheral tissues, complex lipids such as ceramides and sphingolipids act as lipotoxic species at the hypothalamic level to impact metabolism. Here, we will review what is currently known about hypothalamic lipid metabolism and the modulation of energy homeostasis.

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“…Impaired insulin action in other tissues, most notably the liver (4, 5), brain (6,7) and vasculature (8), also play a key role in whole body insulin resistance, and we direct readers to reviews that explore insulin resistance at these sites in detail. We will examine the evidence that common insulin resistance, in the context of muscle and adipose tissue, results from a defect in 'proximal' insulin signaling, which we define for the purposes of this review as the signaling intermediates that lead to the activation of Akt.…”

mentioning

confidence: 99%

Muscle and adipose tissue insulin resistance: malady without mechanism?

Fazakerley

Krycer

Kearney

et al. 2019

Journal of Lipid Research

101

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Insulin resistance is a major risk factor for numerous diseases including Type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of 'common' insulin resistance. Despite considerable effort, the mechanisms that contribute to 'common' insulin resistance are not resolved. There is universal agreement that extracellular perturbations such as nutrient excess, hyperinsulinemia, glucocorticoids or inflammation trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway, but rather is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states such as fasting, and that in the presence of chronic nutrient excess this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort. Insulin resistance is a pathophysiological state where cells display reduced responsiveness to the glucose-lowering activity of insulin. While there are rare cases where mutations in genes associated with insulin signaling or lipodystrophy cause insulin resistance, for the most part insulin resistance is associated with obesity and thus a state of positive energy balance. This form of insulin resistance is frequently associated with hyperinsulinemia, increased waist circumference or visceral adiposity, metabolic dyslipidemia with high triglycerides and low HDL, and hepatic steatosis, features collectively referred to as the metabolic syndrome. We refer to this as "common insulin resistance". Here, both insulin-dependent glucose disposal and suppression of glucose output are impaired, albeit the relative degree of impairment in each process can vary between individuals (1-3).In this review we focus on the literature surrounding insulin resistance in muscle and adipose tissue, and specifically on insulin-stimulated glucose transport into myocytes and adipocytes within these tissues. Impaired insulin action in other tissues, most notably the liver (4, 5), brain (6, 7) and vasculature (8), also play a key role in whole body insulin resistance, and we direct readers to reviews that explore insulin resistance at these sites in detail. We will examine the evidence that common insulin resistance, in the context of muscle and adipose tissue, results from a defect in 'proximal' insulin signaling, which we define for the purposes of this review as the signaling intermediates that lead to the activation of Akt. We argue that common insulin resistance arises ...

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Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

Cited by 77 publications

References 233 publications

Adolescent Obesity: Diet Quality, Psychosocial Health, and Cardiometabolic Risk Factors

Adolescent Obesity: Diet Quality, Psychosocial Health, and Cardiometabolic Risk Factors

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

Muscle and adipose tissue insulin resistance: malady without mechanism?

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