How Obesity Causes Diabetes: Not a Tall Tale

Lazar, Mitchell A.

doi:10.1126/science.1104342

Cited by 494 publications

(352 citation statements)

References 48 publications

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“…Both increased visceral fat and steatotic liver (a probable cause of increased relative liver weight in this modelFunpublished observation) have been implicated in the development of insulin resistance in the context of obesity. [24][25][26] It was thus not surprising that the response to an OGTT was reduced by preventive BJ administration, indicating an improved glucose tolerance possibly related to enhanced insulin sensitivity. In contrast, it was less expected that BJ could not prevent the increased insulinemia or reduced adiponectinemia that develops during this 3-week crucial period in KKA y mice.…”

Section: Discussionmentioning

confidence: 99%

Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice

et al. 2009

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Aim: Biotransformation of blueberry juice by the Serratia vaccinii bacterium gave rise to adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and glucose uptake in muscle cells and adipocytes, but inhibited adipogenesis. This study investigated the antiobesity and antidiabetic potential of biotransformed blueberry juice (BJ) in KKA y mice, rodent model of leptin resistance. Methods: BJ was incorporated in drinking water of KKA y mice. Parameters of body weight, food intake, plasma glucose, insulin, leptin, and adiponectin were measured. Before and after therapy, animals were subjected to an oral glucose tolerance test. At the end of treatment, liver, muscle, kidney, epididymal fat pad, abdominal fat pad, and dorsal fat pad were collected and weighed. Results: Incorporating BJ in drinking water protected young KKA y mice from hyperphagia and significantly reduced their weight gain. Moreover, BJ protected young KKA y mice against the development of glucose intolerance and diabetes mellitus. Chronic BJ administration in obese and diabetic KKA y mice reduced food intake and body weight. This effect could not fully explain the associated antidiabetic effect because BJ-treated mice still showed lower blood glucose level when compared with pair-fed controls. The adipokines pathway also seems to be involved because BJ significantly increased adiponectin levels in obese mice. Conclusions: This study shows that BJ decreases hyperglycemia in diabetic mice, at least in part by reversing adiponectin levels. BJ also protects young pre-diabetic mice from developing obesity and diabetes. Thus, BJ may represent a novel complementary therapy and a source of novel therapeutic agents against diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice

et al. 2009

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“…Lazar commented that 'there are no known survival benefits of morbid obesity' [20], a view that does not consider the potential benefits of short-term weight gain, as against the adverse consequences of chronic weight gain. All the short-term responses of the adipocyte would potentially enhance insulin resistance locally and systemically to direct glucose metabolism to the brain, an essential prerequisite for survival during seasonal adaption.…”

Section: Neel Revisitedmentioning

confidence: 99%

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Scott

Grant

2006

Diabetologia

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The modern epidemic of obesity and insulin resistance with cardiovascular risk factor clustering is related to the development of type 2 diabetes and cardiovascular disease. Over 40 years ago, Neel postulated that insulin resistance should confer survival benefit. Extrapolating Neel's hypothesis, we propose that the cluster of associated abnormalities also confers survival benefit and is related to metabolic responses seen in seasonally responsive animals. Weight gain in preparation for winter is accompanied by a range of acute metabolic changes virtually identical to the long-term changes seen in type 2 diabetes. In seasonal animals the responses are acute, physiological and protective. In man, similar responses that would once have conferred survival benefit have become chronic, pathological and harmful in modern life. We hypothesise that type 2 diabetes and cardiovascular disease in man are the result of chronic and inappropriate pinealhypothalamic-adipocyte interactions biologically related to seasonal change.Keywords Adipocyte . Cardiovascular disease . Circadian and circannual rhythm . Clock genes . Hypothalamus . Inflammation . Insulin resistance . Melatonin . Metabolic syndrome . Seasonality . Type 2 diabetes Neel revisitedThe world is currently in the midst of an epidemic of type 2 diabetes, and around 300 million individuals are predicted to develop this disorder by the year 2025 [1]. The close biological relationship between diabetes and cardiovascular disease has focused attention on the common genetic and environmental antecedents of these conditions-the common soil hypothesis [2]-but the pathophysiological basis of these associations remains obscure. In 1962, Neel proposed the thrifty genotype hypothesis, which postulated that insulin overproduction must at one time have had a beneficial effect, in that it would provide 'an important energy conserving mechanism when food intake was irregular and obesity rare' [3]. Although Neel recognised insulin antagonism rather than insulin resistance, he hypothesised that the combination of obesity with increased insulin (or the presence of insulin antagonists) would lead to the development of diabetes. With hindsight, Neel was essentially speculating on the potential metabolic benefits of insulin resistance. The recognition in the last 20 years of an insulin resistance risk cluster [4] indicates that, under certain circumstances, elements of the risk cluster should also be beneficial to the survival of the organism, a response that, by analogy with Neel's original hypothesis, may coincidentally lead to the development of cardiovascular disease in times of plenty. The development of both insulin resistance and inflammation are physiological responses to increasing adiposity that, by definition, should be beneficial to the survival of the organism. The observation that the chronic metabolic milieu associated with type 2 diabetes is harmful raises the possibility that the adipocyte response to fat loading is beneficial when acute and short-lived, as is o...

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“…These pro-inflammatory cytokines can, in turn, act via transmembrane receptors to phosphorylate serine/threonine kinases, which are known to disrupt insulin signal transduction [1]. Given this pro-inflammatory response and the observation that systemic IL-6 concentrations are elevated in obesity and patients with type 2 diabetes [2], it is generally accepted that IL-6 contributes to obesityinduced insulin resistance [3]. However, the discovery that IL-6 can be produced and released from skeletal muscle during exercise, led many investigators, as reviewed by Pedersen and Febbraio [4], to challenge this concept because insulin action is enhanced in the immediate postexercise period.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

et al. 2010

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Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 −/− ) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 −/− and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 −/− mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 −/− and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 −/− mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 −/− relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

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How Obesity Causes Diabetes: Not a Tall Tale

Cited by 494 publications

References 48 publications

Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice

Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

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