Lipodystrophy in HIV 1-infected patients: lessons for obesity research

Villarroya, Francesc; Domingo, Peré; Giralt, Marta

doi:10.1038/sj.ijo.0803698

Cited by 63 publications

(55 citation statements)

References 140 publications

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“…in response to several stimuli. It is therefore a complex organ controlling energy expenditure, appetite, insulin sensitivity, endocrine and reproductive functions, inflammation, and immunity (53).…”

mentioning

confidence: 99%

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation

Malandrino

Fucho

Weber

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

139

102

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-Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CAR⌬1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that increasing FAO in adipocytes and macrophages improves palmitate-induced derangements. This indicates that enhancing FAO in metabolically relevant cells such as adipocytes and macrophages may be a promising strategy for the treatment of chronic inflammatory pathologies such as obesity and type 2 diabetes.

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mentioning

confidence: 99%

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation

Malandrino

Fucho

Weber

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

139

102

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“…Many examples could be provided: 1) the sedentary postmenopausal woman increasing her waistline without gaining weight as she is losing lean body mass and gaining abdominal fat; 2) the lipodystrophic HIVϩ patient losing subcutaneous fat while gaining visceral fat; 3) the sedentary middle-aged man gaining abdominal fat while losing muscle mass; and 4) the patient with chronic obstructive pulmonary disease losing muscle mass and gaining abdominal fat because he is frail and inactive (317,320,485,599). These represent just a few clinical examples where waist circumference could increase even in the absence of body weight change (BMI).…”

Section: Cardiovascular Diseasementioning

confidence: 99%

Pathophysiology of Human Visceral Obesity: An Update

Tchernof

Després

2013

Physiological Reviews

1,826

1,501

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LTchernof A, Després J-P. Pathophysiology of Human Visceral Obesity: An Update. Physiol Rev 93: 359 -404, 2013; doi:10.1152/physrev.00033.2011.-Excess intra-abdominal adipose tissue accumulation, often termed visceral obesity, is part of a phenotype including dysfunctional subcutaneous adipose tissue expansion and ectopic triglyceride storage closely related to clustering cardiometabolic risk factors. Hypertriglyceridemia; increased free fatty acid availability; adipose tissue release of proinflammatory cytokines; liver insulin resistance and inflammation; increased liver VLDL synthesis and secretion; reduced clearance of triglyceride-rich lipoproteins; presence of small, dense LDL particles; and reduced HDL cholesterol levels are among the many metabolic alterations closely related to this condition. Age, gender, genetics, and ethnicity are broad etiological factors contributing to variation in visceral adipose tissue accumulation. Specific mechanisms responsible for proportionally increased visceral fat storage when facing positive energy balance and weight gain may involve sex hormones, local cortisol production in abdominal adipose tissues, endocannabinoids, growth hormone, and dietary fructose. Physiological characteristics of abdominal adipose tissues such as adipocyte size and number, lipolytic responsiveness, lipid storage capacity, and inflammatory cytokine production are significant correlates and even possible determinants of the increased cardiometabolic risk associated with visceral obesity. Thiazolidinediones, estrogen replacement in postmenopausal women, and testosterone replacement in androgen-deficient men have been shown to favorably modulate body fat distribution and cardiometabolic risk to various degrees. However, some of these therapies must now be considered in the context of their serious side effects. Lifestyle interventions leading to weight loss generally induce preferential mobilization of visceral fat. In clinical practice, measuring waist circumference in addition to the body mass index could be helpful for the identification and management of a subgroup of overweight or obese patients at high cardiometabolic risk.

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“…Lipodystrophy is most commonly seen today in patients treated with retroviral agents (1). Given that they are opposites in terms of adipose tissue mass, it seems paradoxical that lipodystrophy and obesity are accompanied by similar pathological sequelae, including insulin resistance and heightened risk for diabetes, dyslipidemia, and hepatic steatosis (2). At least two consequences of diminished adipose tissue mass in lipodystrophy may contribute to the clinical picture.…”

mentioning

confidence: 99%

Inflammation and adipose tissue macrophages in lipodystrophic mice

Herrero

Shapiro

Nayer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

139

104

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Lipodystrophy and obesity are opposites in terms of a deficiency versus excess of adipose tissue mass, yet these conditions are accompanied by similar metabolic consequences, including insulin resistance, dyslipidemia, hepatic steatosis, and increased risk for diabetes and atherosclerosis. Hepatic and myocellular steatosis likely contribute to metabolic dysregulation in both states. Inflammation and macrophage infiltration into adipose tissue also appear to participate in the pathogenesis of obesity-induced insulin resistance, but their contributions to lipodystrophy-induced insulin resistance have not been evaluated. We used aP2-nSREBP-1c transgenic (Tg) mice, an established model of lipodystrophy, to ask this question. Circulating cytokine elevations suggested systemic inflammation but even more dramatic was the number of infiltrating macrophages in all white and brown adipose tissue depots of the Tg mice; in contrast, there was no evidence of inflammatory infiltrates or responses in any other tissue including liver. Despite there being overt evidence of adipose tissue inflammation, antiinflammatory strategies including salicylate treatment and genetic suppression of myeloid NF-κB signaling that correct insulin resistance in obesity were ineffective in the lipodystrophic mice. We further showed that adipose tissue macrophages (ATMs) in lipodystrophy and obesity are very different in terms of activation state, gene expression patterns, and response to lipopolysaccharide. Although ATMs are even more abundant in lipodystrophy than in obesity, they have distinct phenotypes and likely roles in tissue remodeling, but do not appear to be involved in the pathogenesis of insulin resistance.

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Lipodystrophy in HIV 1-infected patients: lessons for obesity research

Cited by 63 publications

References 140 publications

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation

Pathophysiology of Human Visceral Obesity: An Update

Inflammation and adipose tissue macrophages in lipodystrophic mice

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