Immunoreactive Insulin Levels Are Elevated in the Cerebrospinal Fluid of Genetically Obese Zucker Rats

Lj, Stein; Dm, Dorsa; Dg, Baskin; Dp, Figlewicz; Ikeda, Hitoshi; Sp, Frankmann; Mr, Greenwood; Porte, Daniel; Sc, Woods

doi:10.1210/endo-113-6-2299

Cited by 74 publications

(22 citation statements)

References 9 publications

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“…There are numerous reports of increased fasting plasma insulin (19,49,50); similar observations have been made in CSF of animal models of obesity (51,52). Circulating levels of insulin were relatively low in all groups, presumably due to a combination of the isoflurane-mediated suppression of insulin release (53) and the fasted state of the animals.…”

Section: Discussionsupporting

confidence: 67%

“…Consistent with our data on obese rats, insulin levels in the CSF have previously been reported to be elevated in obese rats (52), sheep (54), and humans (55). Although this appears inconsistent with a recent report on humans (56), that group reported only ratios of plasma to CSF insulin without presenting the actual levels of insulin in the CSF.…”

Section: Discussionsupporting

confidence: 59%

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Reversal of Diet-Induced Obesity Increases Insulin Transport into Cerebrospinal Fluid and Restores Sensitivity to the Anorexic Action of Central Insulin in Male Rats

Begg¹,

Mul

Liu

et al. 2013

Endocrinology

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Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionsupporting

confidence: 59%

Reversal of Diet-Induced Obesity Increases Insulin Transport into Cerebrospinal Fluid and Restores Sensitivity to the Anorexic Action of Central Insulin in Male Rats

Begg¹,

Mul

Liu

et al. 2013

Endocrinology

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“…In the mid-1950s, two studies described an inability of radioactively labeled insulin, injected in the periphery, to be detected in the brains of human or dogs (Elgee, Williams, & Lee, 1954;Haugaard, Vaughan, Haugaard, & Stadie, 1954). However, studies in the 1970s demonstrated that insulin was found in the CSF of numerous species (Stein et al, 1983;Woods & Porte, 1977). From these studies, important characteristics were identified including a strong relationship between the peripheral levels of insulin and levels in the CSF and a limit to the increase of CSF insulin when plasma insulin was at supraphysiological levels.…”

Section: Transport Of Insulin Into the Cnsmentioning

confidence: 99%

Insulin Transport into the Brain and Cerebrospinal Fluid

Begg

2015

Hormones and Transport Systems

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“…The process is saturable, selective for insulin, and regulated (39 -42). Insulin transport into the brain is reduced during fasting (43), by maintenance on a high-fat diet (44), and in genetic and dietary-induced obesity (45,46). Because brain insulin derives from plasma insulin, it should be the case that experimentally induced increases of plasma insulin enter the brain and result in reduced food intake and body weight.…”

Section: Insulin As An Adiposity Signalmentioning

confidence: 99%

The Brain-Gut-Islet Connection

2006

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Peptide signals from the pancreatic islets and the gastrointestinal tract influence the regulation of energy homeostasis by the brain, and the brain in turn influences the secretions of both the islets and the gut. This article focuses on how insulin interacts with the brain to influence food intake, blood glucose, and cognitive behavior. Insulin is secreted in response to changes of ambient glucose, and the levels achieved are directly proportional to body adiposity. Hence, insulin, like leptin, is an adiposity signal. An increased insulin signal in the mediobasal hypothalamus indicates that ample or excess energy is available in the body and elicits responses that limit food intake and reduce hepatic glucose secretion. Increased insulin (and leptin as well) locally within the brain complements other signals that indicate a surfeit of energy in the body, including satiety signals generated by the gut during meals, glucose, and some fatty acids. There is compelling evidence that overlapping intracellular signaling pathways within the mediobasal hypothalamus mediate the overall catabolic response to these diverse metabolic signals. Insulin receptors are also densely expressed in the hippocampus, and insulin acts there to facilitate learning and memory. The function of insulin receptors in other brain areas is poorly understood. Obesity and/or the consumption of diets high in fat render the brain as well as the body insulin resistant. In the hypothalamus, this is manifest as a reduced ability of insulin to reduce food intake and body weight, and in the hippocampus, it is manifest as a reduced ability of insulin to improve learning and/or memory. Diabetes 55 (Suppl. 2):S114 -S121, 2006 T he brain-gut-islet connection refers to the myriad ways in which signals arising in the three arms of this important axis interact among themselves, and at least one overall function of this integrated control system is the regulation of energy homeostasis throughout the body. Many of the interactions of this triad are well known. The brain regulates activity in both the gut and the pancreatic islets directly via the autonomic nervous system and indirectly via changes in food intake and energy expenditure. Peptide hormones and other signals secreted from the gut, in addition to coordinating the digestion and absorption of nutrients, provide the incretin effect that augments prandial insulin secretion. Many of these peptides also serve as critical satiety signals to the brain that limit meal size. Islet hormones influence digestion and control the disposition of ingested nutrients in addition to providing key signals to the brain regarding the level of adiposity and circulating energy. This review focuses on one aspect of this complex network, i.e., the actions of pancreatic insulin within the brain and the pathologies that occur when insulin signaling within the brain is compromised. The topic is timely, with relevant new information appearing almost monthly, and it is also an area of knowledge where the basic tenets are being chall...

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Immunoreactive Insulin Levels Are Elevated in the Cerebrospinal Fluid of Genetically Obese Zucker Rats

Cited by 74 publications

References 9 publications

Reversal of Diet-Induced Obesity Increases Insulin Transport into Cerebrospinal Fluid and Restores Sensitivity to the Anorexic Action of Central Insulin in Male Rats

Reversal of Diet-Induced Obesity Increases Insulin Transport into Cerebrospinal Fluid and Restores Sensitivity to the Anorexic Action of Central Insulin in Male Rats

Insulin Transport into the Brain and Cerebrospinal Fluid

The Brain-Gut-Islet Connection

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