Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults

Kullmann, Stephanie; Heni, Martin; Veit, Ralf; Scheffler, Klaus; Machann, Jürgen; Häring, Hans‐Ulrich; Fritsche, Andreas; Preißl, Hubert

doi:10.2337/dc14-2319

Cited by 134 publications

(170 citation statements)

References 39 publications

(28 reference statements)

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“…44,46 Whether insulin secreted after glucose uptake is responsible for this effect has not been shown conclusively in all studies. 41,42 However, two studies in the past few years have shown similar hypothalamic effects after intranasal insulin, 47,48 underscoring that the human hypothalamus reacts to insulin. Glucoseresponsive and insulinresponsive neurons have been localized to the hypothalamus; therefore, the human hypothalamus probably responds to both signals.…”

Section: Insulin-responsive Brain Areasmentioning

confidence: 95%

“…12 This phenomenon is often referred to as brain insulin resistance. 103,104 The association of increased body weight with impaired insulin action has since been replicated in a number of studies using magnetoencephalography 21,23 and has been localized by fMRI 48,105 and PET. 16 The importance of body weight for brain metabolism is further underlined by the dis covery that insulininduced brain activity in people with obesity normalizes when they lose weight after bariatric surgery.…”

Section: Effects On Peripheral Metabolismmentioning

confidence: 97%

“…39 These include the fusiform gyrus, where the response to food stimuli is attenuated by insulin. 23,49 Furthermore, insulin reduces activity in the prefrontal areas that control human behaviour, 25,42,47,48,50 including the inhibitory control of eating. However, this prefrontal reaction seems to be confined to lean individuals.…”

Section: Insulin-responsive Brain Areasmentioning

confidence: 99%

“…However, this prefrontal reaction seems to be confined to lean individuals. 48 The hippocampus, another insulinresponsive area in humans, [49][50][51] is central for the processing of memory content, particularly memories of a declarative nature. 52 Taken together, neuroimaging studies have localized insulin responses to the hypothalamus and to cortical areas that control higher cognitive functions.…”

Section: Insulin-responsive Brain Areasmentioning

confidence: 99%

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Impaired insulin action in the human brain: causes and metabolic consequences

Heni¹,

et al. 2015

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Over the past few years, evidence has accumulated that the human brain is an insulin-sensitive organ. Insulin regulates activity in a limited number of specific brain areas that are important for memory, reward, eating behaviour and the regulation of whole-body metabolism. Accordingly, insulin in the brain modulates cognition, food intake and body weight as well as whole-body glucose, energy and lipid metabolism. However, brain imaging studies have revealed that not everybody responds equally to insulin and that a substantial number of people are brain insulin resistant. In this Review, we provide an overview of the effects of insulin in the brain in humans and the relevance of the effects for physiology. We present emerging evidence for insulin resistance of the human brain. Factors associated with brain insulin resistance such as obesity and increasing age, as well as possible pathogenic factors such as visceral fat, saturated fatty acids, alterations at the blood-brain barrier and certain genetic polymorphisms, are reviewed. In particular, the metabolic consequences of brain insulin resistance are discussed and possible future approaches to overcome brain insulin resistance and thereby prevent or treat obesity and type 2 diabetes mellitus are outlined.

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Section: Insulin-responsive Brain Areasmentioning

confidence: 95%

Section: Effects On Peripheral Metabolismmentioning

confidence: 97%

Section: Insulin-responsive Brain Areasmentioning

confidence: 99%

Section: Insulin-responsive Brain Areasmentioning

confidence: 99%

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Impaired insulin action in the human brain: causes and metabolic consequences

Heni¹,

et al. 2015

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“…In studies in humans with IR, IN or intravenous insulin application did not induce brain activity in the insulinsensitive brain areas, i.e., the hippocampus, prefrontal cortex, fusiform gyrus, and hypothalamus, as measured by noninvasive brain imaging tools (16,17). Although such evidence for the activation of insulin-sensitive brain regions has not yet been demonstrated after diazoxide administration, the study by Esterson et al (15) adds to the discussion on impaired central regulation of glucose and energy metabolism in type 2 diabetes (11).…”

mentioning

confidence: 99%

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

Gancheva

Roden

2016

Diabetes

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In the past few years, insulin action in the central nervous system (CNS) has attracted a growing interest to better understand the association between neurodegenerative diseases and insulin resistance (IR). Rodent studies have indicated that insulin signaling in the CNS is critical for the suppression of endogenous glucose production (EGP) in the liver (1) and for the regulation of adipose tissue lipolysis (2). These central insulin effects likely depend on PI3K-mediated regulation of several proteins and transcription factors, among which are FoxO1 (3) and AMPK (4), and on the activation of K ATP channels (5) in the hypothalamus (Fig. 1). Recent findings show that subsequent activation of hepatic Kupffer cells and an increase in hepatic interleukin-6 induce signal transducer and activator of transcription 3 (STAT3) phosphorylation to inhibit gluconeogenic gene expression (6). Suppression of lipolysis in adipose tissue by brain insulin signaling reduces the availability of gluconeogenic substrates for the liver, which will further decrease EGP (2). In contrast, studies in dogs did not support the concept of a physiological relevance of CNS insulin action for controlling EGP (7).In humans, intranasal insulin (IN) application has been established as one approach to noninvasively examine brain insulin action in vivo. The IN spray application transiently increases the insulin concentration in liquor (8), likely due to bulk flow within the perivascular space of cerebral blood vessels (9). Using this technique, evidence for the central insulin regulation of systemic lipolysis (10), modulation of liver fat content and hepatic energy metabolism (11), and improvement in whole-body insulin sensitivity (12) has been provided. Interestingly, effects of IN on EGP seem to depend on the experimental conditions with no changes in the fasting state (11) but with reduction during pancreatic clamps (13). Modulation of energy-demanding processes might contribute to the rise in hepatic energy status after IN application. Of note, central insulin regulation of peripheral insulin sensitivity and hepatic energy metabolism was blunted in obese humans and patients with type 2 diabetes (11,12), suggesting that the presence of a combined central and peripheral IR and a dysregulation of a brain-liver cross talk in type 2 diabetes. Nevertheless, IN may have some limitations resulting from variable cerebral insulin delivery and/or peripheral insulin spillover.Another approach to mimic brain insulin action in humans is the administration of the K ATP -channel opener and sulfonylurea drug diazoxide. Dr. Hawkins' group showed that diazoxide treatment can suppress EGP in lean healthy humans, and complementary studies in rodents revealed increased hepatic STAT3 phosphorylation along with reduced hepatic gluconeogenic protein levels (14). The same group now presents a carefully planned and nicely performed follow-up study investigating the effects of diazoxide on EGP in patients with type 2 diabetes. Esterson et al. (15) combined diazoxide admini...

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Diabetes type 2 risk gene Dusp8 is associated with altered sucrose reward behavior in mice and humans

et al. 2020

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Background Dusp8 is the first GWAS‐identified gene that is predominantly expressed in the brain and has previously been linked with the development of diabetes type 2 in humans. In this study, we unravel how Dusp8 is involved in the regulation of sucrose reward behavior. Methods Female, chow‐fed global Dusp8 WT and KO mice were tested in an observer‐independent IntelliCage setup for self‐administrative sucrose consumption and preference followed by a progressive ratio task with restricted sucrose access to monitor seeking and motivation behavior. Sixty‐three human carriers of the major C and minor T allele of DUSP8 SNP rs2334499 were tested for their perception of food cues by collecting a rating score for sweet versus savory high caloric food. Results Dusp8 KO mice showed a comparable preference for sucrose, but consumed more sucrose compared to WT mice. In a progressive ratio task, Dusp8 KO females switched to a “trial and error” strategy to find sucrose while control Dusp8 WT mice kept their previously established seeking pattern. Nonetheless, the overall motivation to consume sucrose, and the levels of dopaminergic neurons in the brain areas NAcc and VTA were comparable between genotypes. Diabetes‐risk allele carriers of DUSP8 SNP rs2334499 preferred sweet high caloric food compared to the major allele carriers, rating scores for savory food remained comparable between groups. Conclusion Our data suggest a novel role for Dusp8 in the perception of sweet high caloric food as well as in the control of sucrose consumption and foraging in mice and humans.

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Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults

Cited by 134 publications

References 39 publications

Impaired insulin action in the human brain: causes and metabolic consequences

Impaired insulin action in the human brain: causes and metabolic consequences

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

Diabetes type 2 risk gene Dusp8 is associated with altered sucrose reward behavior in mice and humans

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