The role of leptin resistance in the lipid abnormalities of aging

Wang, Zhuo-Wei; Pan, Wei‐Jian; Lee, Young; Kakuma, Tatsuyuki; Zhou, Yanting; Unger, Roger H

doi:10.1096/fj.00-0310com

Cited by 143 publications

(111 citation statements)

References 27 publications

(32 reference statements)

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“…32,41,42 Socs3 has been also proposed as a potential mediator of the insulin resistance induced by some hormones. 43,44 SOCS proteins disrupt insulin signaling by binding to the insulin receptor and/or by targeting Irs1 Periodontitis and aortic insulin signaling D Ekuni et al Figure 3 Cross-sections of descending aorta in the control and periodontitis groups.…”

Section: Discussionmentioning

confidence: 99%

Effects of periodontitis on aortic insulin resistance in an obese rat model

Ekuni

Tomofuji

Irie

et al. 2010

Laboratory Investigation

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The combination of obesity and its associated risk factors, such as insulin resistance and inflammation, results in the development of atherosclerosis. However, the effects of periodontitis on atherosclerosis in an obese body remain unclear. The aim of the study was to investigate the effects of ligature-induced periodontitis in Zucker fatty rats on initiation of atherosclerosis by evaluating aortic insulin resistance. Zucker fatty rats (n ¼ 24) were divided into two groups. In the periodontitis group, periodontitis was ligature-induced for 4 weeks, whereas the control group was left unligated. After the 4-week experimental period, descending aorta was used for measuring the levels of lipid deposits, immunohistochemical analysis, and evaluation of gene expression. Levels of serum C-reactive protein (CRP), tumor necrosis factora (TNF-a), and insulin were also measured. Rats in the periodontitis group had significantly enhanced lipid deposits in the aorta, but not in the control group. Expression of suppressor of cytokine signaling 3, vascular cell adhesion molecule 1, reactive oxygen species, nitrotyrosine, and endothelin-1 in the periodontitis group was more intense than that in the control group. Significantly decreased levels of phosphatidylinositol 3-kinase (Pi3k) catalytic b-polypeptide (Pi3kcb), Pi3kp85, and insulin receptor substrate 1 and 2 were observed in the periodontitis group. Levels of serum CRP and TNF-a were significantly increased in the periodontitis group. Under insulin-stimulated conditions, aorta in the periodontitis group altered the Akt phosphorylation. Periodontitis in obesity induced the initial stage of atherosclerosis and disturbed aortic insulin signaling.

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Section: Discussionmentioning

confidence: 99%

Effects of periodontitis on aortic insulin resistance in an obese rat model

Ekuni

Tomofuji

Irie

et al. 2010

Laboratory Investigation

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“…Adipogenesis and the intrinsic functional dynamics of preadipocytes en route to develop into fully functional mature adipocytes have been documented to decline markedly with age (51,52). In particular, the capacity of preadipocytes to proliferate, differentiate, and confer resistance to cell death is severely blunted with age (51,53).…”

Section: Figurementioning

confidence: 99%

Adipose tissue remodeling and obesity

Sun¹,

Kusminski²,

Scherer³

2011

J. Clin. Invest.

1,585

1,381

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To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth. IntroductionAdipose tissue (AT) can respond rapidly and dynamically to alterations in nutrient deprivation and excess through adipocyte hypertrophy and hyperplasia, thereby fulfilling its major role in wholebody energy homeostasis. AT remodeling is an ongoing process that is pathologically accelerated in the obese state, and thus, features such as reduced angiogenic remodeling, ECM overproduction, a heightened state of immune cell infiltration and subsequent proinflammatory responses prevail in many obese fat-pads (1). However, not all AT expansion is necessarily associated with pathological changes. The concept of the "metabolically healthy obese" state (2) suggests that some individuals can preserve systemic insulin sensitivity on the basis of "healthy" AT expansion, bypassing all of the aforementioned pathological consequences associated with obesity (3), thereby also avoiding the obesity-associated lipotoxic side effects. Many physiologically relevant processes important for human AT remodeling can be studied in rodent models, with the added advantage that processes related to AT expansion and reduction can occur at an extremely rapid rate. A 24-hour fast in a mouse is associated with a dramatic loss of AT mass and an acute remodeling process that involves rapid infiltration of macrophages; moreover, merely 24 to 48 hours of exposure to a high-fat diet (HFD) can cause a prompt increase in adipocyte size (4). AT is therefore an ideal model system to study rapid alterations in tissue expansion and reduction, as it adapts to a differential nutrient supply. Here, we will focus on key aspects of the intricate dynamics of AT remodeling and subsequent inflammatory consequences that arise from obesity.

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“…Finally, old age is accompanied by profound leptin resistance (9,10), which may explain the increase in total body fat, the elevated lipid content of nonadipose tissues, and the reduction in lean body mass in elderly patients.…”

Section: Lipotoxic Diseasesmentioning

confidence: 99%

Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover.

2001

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A recently identified function of leptin is to protect nonadipose tissues from the nonoxidative metabolic products of long-chain fatty acids (FAs) during periods of overnutrition by increasing the ␤-oxidative metabolism of surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as ceramide increase in nonadipose tissues, including the pancreatic islets and heart, and cause nitric oxide-mediated lipotoxicity and lipoapoptosis. The triacylglycerol content in nonadipocytes provides a useful index of overall nonoxidative metabolism. In normal animal tissue, triacylglycerol is maintained within a narrow range; even when the caloric intake is excessive, compensatory FAinduced upregulation of oxidation prevents overaccumulation. However, if leptin is deficient or if leptin receptors (Ob-R) are nonfunctional, this autoregulatory system does not operate, and triacylglycerol content rises in nonadipose tissues. This provides a source of excess FAs that enter potentially toxic pathways of nonoxidative metabolism leading to apoptosis of certain tissues. FA overload in skeletal muscle causes insulin resistance; in myocardium, it impairs cardiac function; and in pancreatic islets, it causes ␤-cell dysfunction, apoptosis, and diabetes. All abnormalities in these tissues can be blocked by troglitazone, an inhibitor of FA accumulation. Diabetes 50 (Suppl. 1):S118-S121, 2001T he evolution of the adipocyte may well constitute one of the most transforming events in phylogenetic development. As proposed in the "thrifty gene" hypothesis of Neel (1), the ability to preload calories and to store them in the form of triacylglycerol for use during famine and/or exertion improved survival for many species. Recent work from this lab (2) suggests that the adipocytes have an additional function, namely, to protect nonadipocytes, which have only a limited capacity to store triacylglycerol, from excessive accumulation of lipids and their entry into nonoxidative metabolic pathways. This protection requires the permissive action of the adipocyte hormone leptin (3), which, as will be explained below, reduces lipogenesis and increases oxidation in nonadipocytes during overnutrition, dissipating the unneeded energy of the fatty acid (FA) excess as heat (4). This limits FA entry into potentially toxic nonoxidative metabolic pathways (5). LIPOTOXIC DISEASESLipotoxicity refers to the tissue disease that may occur when FA spillover in excess of the oxidative needs of those tissues enhances metabolic flux into harmful pathways of nonoxidative metabolism. Although lipotoxicity is not currently recognized as a clinical entity in obese humans, human disorders of FA metabolism exhibit clinical syndromes similar to those of the obese rodent. It seems reasonable, therefore, to group them under the rubric of lipotoxic diseases. The disorders in which lipotoxicity due to FA overflow is suspected include congenital generalized lipodystrophy (CGL), obesity due to mutations in the leptin or leptin r...

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The role of leptin resistance in the lipid abnormalities of aging

Cited by 143 publications

References 27 publications

Effects of periodontitis on aortic insulin resistance in an obese rat model

Effects of periodontitis on aortic insulin resistance in an obese rat model

Adipose tissue remodeling and obesity

Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover.

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