Effects of chronic intrahypothalamic infusion of insulin on food intake and diurnal meal patterning in the rat.

McGowan, Malcolm K.; Andrews, Karolyn M.; Kelly, Joe; Grossman, Sebastian P.

doi:10.1037/0735-7044.104.2.373

Cited by 90 publications

(33 citation statements)

References 34 publications

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“…Further, the teleologic rationale for a specialized transport system for insulin across the choroid into CSF is unclear, since this uptake results in relatively low CSF insulin levels, and recent studies have established that infusion of insulin into CSF is an inefficient means for its delivery into the brain. For example, 100-1,000-fold greater CSF infusion rates are required to achieve effects on food intake comparable to those resulting from direct intrahypothalamic insulin delivery (29 pression offood intake), regulation ofneuropeptide biosynthesis and catecholamine metabolism, and activation of the sympathetic nervous system. Collectively, these central actions promote a state of negative energy balance, favoring weight loss.…”

Section: Discussionmentioning

confidence: 99%

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.

Baura¹,

Foster²,

Porte³

et al. 1993

J. Clin. Invest.

436

224

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By acting in the central nervous system, circulating insulin may regulate food intake and body weight. We have previously shown that the kinetics of insulin uptake from plasma into cerebrospinal fluid (CSF) can best be explained by passage through an intermediate compartment. To determine if transport kinetics into this compartment were consistent with an insulin receptor-mediated transport process, we subjected overnight fasted, anesthetized dogs to euglycemic intravenous insulin infusions for 90 min over a wide range of plasma insulin levels (69-5,064 ,U/ml) (n = 10). Plasma and CSF samples were collected over 8 h for determination of immunoreactive insulin levels, and the kinetics of insulin uptake from plasma into CSF were analyzed using a compartmental model with three components (plasma --intermediate compartment -CSF). By sampling frequently during rapid changes of plasma and CSF insulin levels, we were able to precisely estimate three parameters (average standard deviation 14%) characterizing the uptake of insulin from plasma, through the intermediate compartment and into CSF (klk2); insulin entry into CSF and insulin clearance from the intermediate compartment (k2 + k3); and insulin clearance from CSF (k4). At physiologic plasma insulin levels (80±7.4,gU/ml), klk2 was determined to be 10.7 X 10'±+1.3 X 10-6 min2. With increasing plasma levels, however, k1k2 decreased progressively, being reduced sevenfold at supraphysiologic levels (5,064 ,U/ml). The apparent KM of this saturation curve was 742 uUU/ml ( -5 nM). In contrast, the rate constants for insulin removal from the intermediate compartment and from CSF did not vary with plasma insulin (k2 + k3 = 0.011±0.0019 min' and k4 = 0.046±0.021 min').We conclude that delivery of plasma insulin into the central nervous system is saturable, and is likely facilitated by an insulin-receptor mediated transport process. (J. Clin. Invest. 1993.

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Section: Discussionmentioning

confidence: 99%

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.

Baura¹,

Foster²,

Porte³

et al. 1993

J. Clin. Invest.

436

224

View full text Add to dashboard Cite

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“…Insulin acts as a satiety signal, stimulating the central nervous regulatory system responsible for food intake and body weight control (McGowan et al 1990). At the cellular level, insulin action is characterized by several effects, including changes in vesicle trafficking, stimulation of protein kinases and phosphatases, control of cellular growth and differentiation, and activation or repression of transcription.…”

Section: Introductionmentioning

confidence: 99%

Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition

Rodrigues¹,

Souza²,

Silva³

et al. 2007

Journal of Endocrinology

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Experimental and clinical studies have demonstrated that early postnatal overnutrition represents a risk factor for later obesity and associated metabolic and cardiovascular disturbance. In the present study, we assessed the levels of glucose transporter 4 (GLUT-4), GLUT-1, insulin receptor (IR), IR substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K) and Akt expression, as well as insulin-stimulated glucose transport and Akt activity in adipocytes from adult rats previously raised in small litters (SL). The normal litter (NL) served as control group. We also investigated glycemia, insulinemia, plasma lipid levels, and glucose tolerance. Our data demonstrated that early postnatal overfeeding induced a persistent hyperphagia accompanied by a significant increase in body weight until 90 days of age. The SL group also presented a significant increase (w42%) in epidydimal fat weight. Blood glucose, plasma insulin, and lipid levels were similar among the animals from the SL and NL groups. While insulin-stimulated glucose uptake was approximately twofold higher in adipocytes from the NL group, no stimulatory effect was observed in the SL group. The impaired insulin-stimulated glucose transport in adipose cells from the SL rats was associated with a significant decrease in GLUT-4, IRS-1 and PI3K expression, and Akt activity. In contrast, IR and Akt expression in adipocytes was not different between the SL and NL groups. Despite these alterations, our results showed no differences in glucose tolerance test in rats raised under different feeding conditions. Our findings reinforce a potent and long-term effect of neonatal overfeeding, which can program major changes in the metabolic regulatory mechanisms.

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“…In a subsequent review, Porte and Woods (94) proposed that insulin served as an "adiposity signal" whose levels in the brain reflected the size of adipose stores integrated over time and which served to complete a negative feedback loop that links the behavior of feeding with size of adipose stores, such that adipose mass remains fairly constant in adults over a relatively long time. Many studies over the intervening decades have essentially validated this basic concept (e.g., 3,4,15,25,84). In the mid-90s, a second candidate adiposity signal, Ob-protein or leptin, was identified (133), and the function of these two signals appears to be similar.…”

mentioning

confidence: 99%

Adiposity signals and food reward: expanding the CNS roles of insulin and leptin

Figlewicz

2003

American Journal of Physiology-Regulatory, Integrative and Comp

190

135

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Figlewicz, Dianne P. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 284: R882-R892, 2003;10.1152/ajpregu.00602.2002The hormones insulin and leptin have been proposed to act in the central nervous system (CNS) as adiposity signals as part of a theoretical negative feedback loop that senses the caloric stores of an animal and orchestrates adjustments in energy balance and food intake. Much research has provided support for both the existence of such a feedback loop and the specific roles that insulin and leptin may play. Most studies have focused on hypothalamic sites, which historically are implicated in the regulation of energy balance, and on the brain stem, which is a target for neural and humoral signals relating to ingestive acts. More recent lines of research, including studies from our lab, suggest that in addition to these CNS sites, brain reward circuitry may be a target for insulin and leptin action. These studies are reviewed together here with the goals of providing a historical overview of the findings that have substantiated the originally hypothesized negative feedback model and of opening up new lines of investigation that will build on these findings and allow further refinement of the model of adiposity signal/CNS feedback loop. The understanding of how motivational circuitry and its endocrine or neuroendocrine modulation contributes to normal energy balance regulation should expand possibilities for future therapeutic approaches to obesity and may lead to important insights into mental illnesses such as substance abuse or eating disorders. central nervous system; dopamine; food intake FROM HISTORICAL PERSPECTIVE TO MODERN PERSPECTIVEIn 1979, Porte, Woods, and colleagues (130) made the observation that putting a small amount of the metabolic hormone insulin directly into the cerebrospinal fluid (CSF) of nonhuman primates resulted in a significant decline in the animals' food intake and body weight. This observation was made in the context of ongoing studies in the field that suggested that a circulating humoral factor or factors could regulate both size of individual meals, as well as food intake and body weight, over a longer time course (31,83,90,117). In a subsequent review, Porte and Woods (94) proposed that insulin served as an "adiposity signal" whose levels in the brain reflected the size of adipose stores integrated over time and which served to complete a negative feedback loop that links the behavior of feeding with size of adipose stores, such that adipose mass remains fairly constant in adults over a relatively long time. Many studies over the intervening decades have essentially validated this basic concept (e.g., 3, 4, 15, 25, 84). In the mid-90s, a second candidate adiposity signal, Ob-protein or leptin, was identified (133), and the function of these two signals appears to be similar. A major research focus has been on the actions of these two hormones at the medial hypothalamus, which historically has be...

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Effects of chronic intrahypothalamic infusion of insulin on food intake and diurnal meal patterning in the rat.

Cited by 90 publications

References 34 publications

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.

Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition

Adiposity signals and food reward: expanding the CNS roles of insulin and leptin

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