Mechanisms of Leptin Action and Leptin Resistance

Myers, Martin G.; Cowley, Michael A.; Münzberg, Heike

doi:10.1146/annurev.physiol.70.113006.100707

Cited by 915 publications

(877 citation statements)

References 127 publications

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“…The augmented response to leptin is not likely to be related to an increase in Ob-Rb expression, because we observed no differences in receptor expression as determined by mRNA levels. In fact, the augmented response is surprising given the fact that obesity is typically associated with leptin resistance, particularly in the brain (31,32). The altered response of macrophages may be related to either activation of resident cells or recruitment of a new population of circulating cells.…”

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Obesity is associated with increased prevalence and severity of asthma. Adipose tissue macrophages can contribute to the systemic proinflammatory state associated with obesity. However, it remains unknown whether alveolar macrophages have a unique phenotype in overweight/obese patients with asthma. Objectives: We hypothesized that leptin levels would be increased in the bronchoalveolar lavage fluid from overweight/obese subjects and, furthermore, that leptin would alter the response of alveolar macrophages to bacterial LPS. Methods: Forty-two subjects with asthma and 46 healthy control subjects underwent research bronchoscopy. Bronchoalveolar lavage fluid from 66 was analyzed for the level of cellular inflammation, cytokines, and soluble leptin. Cultured primary macrophages from 22 subjects were exposed to LPS, leptin, or leptin plus LPS. Cytokines were measured in the supernatants. Measurements and Main Results: Leptin levels were increased in overweight/obese subjects, regardless of asthma status (P ¼ 0.013), but were significantly higher in overweight/obese subjects with asthma. Observed levels of tumor necrosis factor-a were highest in overweight/obese subjects with asthma. Ex vivo studies of primary alveolar macrophages indicated that the response to LPS was most robust in alveolar macrophages from overweight/obese subjects with asthma and that preexposure to high-dose leptin enhanced the proinflammatory response. Leptin alone was sufficient to induce production of proinflammatory cytokines from macrophages derived from overweight/obese subjects with asthma. Conclusions: Ex vivo studies indicate that alveolar macrophages derived from overweight/obese subjects with asthma are uniquely sensitive to leptin. This macrophage phenotype, in the context of higher levels of soluble leptin, may contribute to the pathogenesis of airway disease associated with obesity.Keywords: tumor necrosis factor-a; leptin; innate immunity; lipopolysaccharide; environmental lung disease There is an increased risk of developing asthma in individuals who are overweight and obese (subsequently referred to as overweight/obese) (1-5). The risk of asthma increases steadily with increasing body mass index (BMI) and is higher in women (1, 6). Furthermore, BMI negatively impacts asthma quality of life scores, asthma control scores, severity of exacerbations, and asthma-related hospitalizations (6-9). Together, these studies suggest a role of obesity in the pathogenesis of asthma. However, the mechanisms by which obesity may contribute to airway disease remain poorly understood.Evidence suggests that adipose tissue is metabolically active, participating not only in energy homeostasis but also in inflammation (12). Adipose tissue secretes biologically active cytokines, including tumor necrosis factor (TNF)-a and IL-6, as well as adipokines, including leptin, adiponectin, plasminogen activator inhibitor (PAI)-1, and resistin (10, 11). Obesity is associated with systemic inflammation, which is characterized by elevated serum levels of...

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Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

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“…For example, leptin enhances hippocampal synaptic plasticity and improves performance of rodents in learning and memory tasks (Harvey, 2007). As diabetes is associated with leptin resistance (Myers et al, 2008), it is possible that impaired leptin signaling contributes to the diet-induced deficits in hippocampal plasticity in the present study. Another such peptide, ghrelin, has previously been shown to promote spinogenesis and learning in the hippocampus (Diano et al, 2006).…”

mentioning

confidence: 69%

Diet‐induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle‐aged rats

et al. 2008

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Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for eight months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced LTP at Schaffer collateral -CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high energy diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines. Keywordsfructose; hippocampus; long-term potentiation; obesity; diabetes; BDNF; high-fat diet Dietary energy intake has increased steadily in Western societies during the past 50 years resulting in increased obesity, diabetes and cardiovascular disease (Everitt et al., 2006). Simple sugars and saturated fats are believed to be major components of the Western diet that promote obesity and insulin resistance (Gross et al., 2004). Data from clinical, epidemiological and animal studies have suggested that excessive energy intake adversely affects the brain, particularly during aging. Studies suggest that individuals with a high energy intake are at increased risk of Alzheimer's disease (Luschsinger et al., 2002). Animal studies have shown that high-calorie diets impair the structure and function of the hippocampus, a brain region critical for learning and memory (Farr et al., 2008;Greenwood and Winocur, 1990;Kanoski et al., 2007;Molteni et al., 2002;Winocur and Greenwood, 1999;Wu et al., 2004). The adverse effects of high calorie diets on learning and memory have been associated with impaired hippocampal synaptic plasticity and neurogenesis (Farr et al., 2008;Lindqvist et al., 2006), suggesting that the hippocampus may be particularly sensitive to changes in dietary energy intake. In the present study we fed rats a diet high in saturated fats and simple sugars, and supplemented their water with high-fructose corn syrup. This diet increased fasting blood glucose levels and serum cholesterol and triglycerides. Additionally, we found that the diet impairs hippocampusdependent learning, synaptic plasticity, and dendritic spine density. These adverse effects on brain function were associated with reduced levels of BDNF in the hippocampus and suggest that "Western" diets impair synaptic function and cognition by a mechanism involving reductions in BDNF and atrophy of dendritic spines. Detailed description of the methods and procedures us...

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“…It was initially thought that this feedback loop could be used to inhibit food intake in the obese, but clinical trials of leptin analogues had little success, because endogenous leptin has since been found to be elevated in the obese, who often exhibit leptin resistance. 35 The adipokine has since been attributed to being a signal for energy deficiency, rather than a signal to lose weight, as excessive weight loss will result in decreased leptin levels and a consequential increase in food intake. 36,37 Since the characterisation of leptin, many other adipokines have been discovered, such as apelin, visfatin, chemerin and vaspin, with adiponectin being the most fully studied.…”

Section: Adipose Tissue a Paracrine And Endocrine Organmentioning

confidence: 99%

Once fat was fat and that was that : our changing perspectives on adipose tissue

Ferris

Crowther

2011

CardioVascular Journal of Africa

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Past civilisations saw excess body fat as a symbol of wealth and prosperity as the general population struggled with food shortages and famine. Nowadays it is recognised that obesity is associated with co-morbidities such as cardiovascular disease and diabetes. Our views on the roll of adipose tissue have also changed, from being solely a passive energy store, to an important endocrine organ that modulates metabolism, immunity and satiety. The relationship between increased visceral adiposity and obesity-related co-morbidities has lead to the recognition that variation in fat distribution contributes to ethnic differences in the prevalence of obesity-related diseases. Our current negative view of adipose tissue may change with the use of pluripotent adipose-derived stromal cells, which may lead to future autologous stem cell therapies for bone, muscle, cardiac and cartilage disorders. Here, we briefly review the concepts that adipose tissue is an endocrine organ, that differences in body fat distribution underline the aetiology of obesity-related co-morbidities, and the use of adipose-derived stem cells for future therapies.

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Mechanisms of Leptin Action and Leptin Resistance

Cited by 915 publications

References 127 publications

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Diet‐induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle‐aged rats

Once fat was fat and that was that : our changing perspectives on adipose tissue

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