Starvation and Triglycerides Reverse the Obesity-Induced Impairment of Insulin Transport at the Blood-Brain Barrier

Urayama, Akihiko; Banks, William A.

doi:10.1210/en.2008-0008

Cited by 108 publications

(104 citation statements)

References 43 publications

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“…Thus the question arises as to whether insulin resistance may be contributing to the leptin resistance observed with fructose feeding. This possibility seems unlikely, however, in light of the recent finding that in contrast to their effects on leptin, elevated circulating TGs enhance BBB insulin transport (67).…”

Section: Is the Phenomenon Specific To Fructose?mentioning

confidence: 98%

Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on “Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding,” by Shapiro et al.

Vasselli¹

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Brief Historical PerspectiveTHE CONCEPT OF LEPTIN RESISTANCE appeared in the literature almost as soon as the hormone itself was discovered. For purposes of our discussion, leptin resistance will be defined as, "reduced or absent responsiveness to the feeding and body weight inhibitory effects of the hormone in obese individuals in comparison with normal (lean) controls." Two early reports, demonstrating significant correlations in humans between circulating leptin levels and increasing adiposity, came to the conclusion that resistance to the purported regulatory role of leptin on appetite and body weight must be induced as levels of the hormone increase (18,43). In short order, the concept of leptin resistance was given experimental support by the finding of decreased ratios of cerebrospinal fluid vs. plasma levels of leptin in obese humans (14,61). Parallel findings were made at almost the same time in obese rodents (24,73). Whatever its mechanism, the notion of leptin resistance provided a ready explanation for excess body fat in individuals in the face of extremely high circulating leptin levels. Despite rather compelling initial observations, the notion of leptin resistance remained controversial at early stages of its advancement (4), or was reinterpreted in terms of individual variability in genetically determined leptin response thresholds (56). In fairness, these reviews appeared prior to experimental evidence demonstrating the existence of leptin resistance in obese humans (28,31,44). Moreover, findings of significant associations between leptin receptor gene polymorphisms and body mass index, fat mass, and eating behavior in humans were subsequently published (15, 21, 69). Nevertheless, it was not until experimental demonstrations of the phenomenon in outbred animals and subsequent analyses of the biological mechanisms involved that the notion gained widespread acceptance.Experimental leptin resistance was first demonstrated in wild-type mice made obese on a high-fat (HF) diet (13). This was followed by numerous reports of leptin resistance in diet-induced obese rodent models in response to central and/or peripheral administration of leptin (25,70,72). More careful behavioral analysis of the sequence of events in the induction of diet-induced leptin resistance revealed what appeared to be a two-step process over successive weeks of HF feeding, with the expression of first peripheral, and then central, leptin resistance (23, 39). Parallel work on potential biological mechanisms underlying leptin resistance revealed the saturation at elevated circulating leptin levels of an active blood-brain barrier (BBB) leptin transport mechanism (7, 12), reduced hypothalamic leptin receptor expression (42,66), and the inhibition of hypothalamic leptin receptor signal transducer and activator of transcription-3 (STAT-3) second messenger signaling (23) in HF-fed animals. Evidence indicates that these biological events may well parallel the behavioral sequence described above in the induction of leptin resistance (23, ...

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Section: Is the Phenomenon Specific To Fructose?mentioning

confidence: 98%

Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on “Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding,” by Shapiro et al.

Vasselli¹

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Moreover, it was recently demonstrated that astrocytic IR deficiency decreases nutrient availability in the CNS, impairing systemic glucose homeostasis through the reduction in glucose-induced activation of glucose-sensing neurons [34]. Several studies have proposed that insulin transport into the brain is impaired in obesity and diabetes [51,57,58]. However, the lower rate of radiolabeled insulin transport observed in obese mice could be a result of hyperinsulinemia in these animals.…”

Section: Insulin Transport Into the Brainmentioning

confidence: 99%

“…Metabolic insults can reduce the ratio of insulin uptake into the brain, and it is thought that insulin transport is impaired under those circumstances [51,57,58]. However, in obese animals, brain insulin resistance is also observed at the level of hypothalamic signaling pathways with a decrease in PI3K-Akt response following insulin administration [91].…”

Section: Impaired Insulin Signaling In the Brain Upon The Onset Of Obmentioning

confidence: 99%

Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

Chen

Balland

Cowley³

2017

Neuroendocrinology

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The central link between obesity and type 2 diabetes is the development of insulin resistance. To date, it is still not clear whether hyperinsulinemia causes insulin resistance, which underlies the pathogenesis of obesity-associated type 2 diabetes, owing to the sophisticated regulatory mechanisms that exist in the periphery and in the brain. In recent years, accumulating evidence has demonstrated the existence of insulin resistance within the hypothalamus. In this review, we have integrated the recent discoveries surrounding both central and peripheral insulin resistance to provide a comprehensive overview of insulin resistance in obesity and the regulation of systemic glucose homeostasis. In particular, this review will discuss how hyperinsulinemia and hyperleptinemia in obesity impair insulin sensitivity in tissues such as the liver, skeletal muscle, adipose tissue, and the brain. In addition, this review highlights insulin transport into the brain, signaling pathways associated with hypothalamic insulin receptor expression in the regulation of hepatic glucose production, and finally the perturbation of systemic glucose homeostasis as a consequence of central insulin resistance. We also suggest future approaches to overcome both central and peripheral insulin resistance to treat obesity and type 2 diabetes.

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“…Levels of glucose are detected by nutrientsensing systems in both the periphery (15,41,56,130,212) and brain (111,130), with consequences to energy balance and fuel utilization in the periphery. TGs may even be sensed via their putative effects on leptin and insulin transport across the blood-brain barrier (13,108,232). However, FFAs present the most intriguing of these nutrients, as their impact on energy balance regulation may be most relevant during the dynamic metabolic state of overfeeding.…”

Section: Enhanced Metabolic Flexibility: Improved Nutrient Clearancementioning

confidence: 99%

Biology's response to dieting: the impetus for weight regain

MacLean

Bergouignan

Cornier

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

374

326

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Dieting is the most common approach to losing weight for the majority of obese and overweight individuals. Restricting intake leads to weight loss in the short term, but, by itself, dieting has a relatively poor success rate for long-term weight reduction. Most obese people eventually regain the weight they have worked so hard to lose. Weight regain has emerged as one of the most significant obstacles for obesity therapeutics, undoubtedly perpetuating the epidemic of excess weight that now affects more than 60% of U.S. adults. In this review, we summarize the evidence of biology's role in the problem of weight regain. Biology's impact is first placed in context with other pressures known to affect body weight. Then, the biological adaptations to an energy-restricted, low-fat diet that are known to occur in the overweight and obese are reviewed, and an integrative picture of energy homeostasis after long-term weight reduction and during weight regain is presented. Finally, a novel model is proposed to explain the persistence of the "energy depletion" signal during the dynamic metabolic state of weight regain, when traditional adiposity signals no longer reflect stored energy in the periphery. The preponderance of evidence would suggest that the biological response to weight loss involves comprehensive, persistent, and redundant adaptations in energy homeostasis and that these adaptations underlie the high recidivism rate in obesity therapeutics. To be successful in the long term, our strategies for preventing weight regain may need to be just as comprehensive, persistent, and redundant, as the biological adaptations they are attempting to counter. energy restriction; diet-induced obesity; obesity prone; weight loss; energy balance IN THE UNITED STATES, OVER 60% of adults and close to 20% of children are overweight or obese (35,174). A number of effective weight loss strategies are available, but most are only transiently effective over a period of 3 to 6 mo. Less than 20% of individuals that have attempted to lose weight are able to achieve and maintain a 10% reduction over a year (128). Over one-third of lost weight tends to return within the first year, and the majority is gained back within 3 to 5 years (3,246). A number of reasons have been proposed for the high incidence of weight regain (69,246), and several point to the biological response to weight loss.The objective of this review is to examine the role of this biological response in the process of weight regain. Biological regulation is first discussed in relation to other nonbiological pressures that affect body weight as weight is gained, lost, and regained. The specific biological adaptations to the most common form of dieting, an energy-restricted low-fat diet, are then discussed in more detail. Previous reviews provide extensive descriptions of the normal adaptive response to energy restriction. We do not attempt to recapitulate those efforts here. Rather, the unique perspective of this review summarizes those adaptations that have been confirmed o...

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Starvation and Triglycerides Reverse the Obesity-Induced Impairment of Insulin Transport at the Blood-Brain Barrier

Cited by 108 publications

References 43 publications

Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on “Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding,” by Shapiro et al.

Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on “Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding,” by Shapiro et al.

Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

Biology's response to dieting: the impetus for weight regain

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