The Relationship of Omental and Subcutaneous Adipocyte Size to Metabolic Disease in Severe Obesity

O’Connell, Jean; Lynch, Lydia; Cawood, Tom; Kwaśnik, Anna; Nolan, Niamh; Geoghegan, Justin; McCormick, Aiden; O’Farrelly, Cliona; O’Shea, Donal

doi:10.1371/journal.pone.0009997

Cited by 180 publications

(136 citation statements)

References 46 publications

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“…Importantly, there is a positive correlation between adipocyte hypertrophy and adipocyte necrosis in visceral fat of obese mice and humans (21). In agreement with previous work (25), MHO individuals possessed an average adipocyte diameter of ;75 mm, but metabolically unhealthy obese (MUO) individuals had significantly larger adipocytes, which were ;85 mm in diameter, thus representing almost a 15% increase in adipocyte size (Fig. 4A).…”

Section: Endogenous Oils Derived From Visceral Fat Of Mho Metabolicasupporting

confidence: 91%

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Endogenous Oils Derived From Human Adipocytes Are Potent Adjuvants That Promote IL-1α–Dependent Inflammation

et al. 2014

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Obesity is characterized by chronic inflammation associated with neutrophil and M1 macrophage infiltration into white adipose tissue. However, the mechanisms underlying this process remain largely unknown. Based on the ability of oil-based adjuvants to induce immune responses, we hypothesized that endogenous oils derived from necrotic adipocytes may function as an immunological "danger signal." Here we show that endogenous oils of human origin are potent adjuvants, enhancing antibody responses to a level comparable to Freund's incomplete adjuvant. The endogenous oils were capable of promoting interleukin (IL)-1a-dependent recruitment of neutrophils and M1-like macrophages, while simultaneously diminishing M2-like macrophages. We found that endogenous oils from subcutaneous and omental adipocytes, and from healthy and unhealthy obese individuals, promoted comparable inflammatory responses. Furthermore, we also confirmed that white adipocytes in visceral fat of metabolically unhealthy obese (MUO) individuals are significantly larger than those in metabolically healthy obese individuals. Since adipocyte size is positively correlated with adipocyte death, we propose that endogenous oils have a higher propensity to be released from hypertrophied visceral fat in MUO individuals and that this is the key factor in driving inflammation. In summary, this study shows that adipocytes contain a potent oil adjuvant which drives IL1a-dependent proinflammatory responses in vivo.Obesity is characterized by chronic, low-grade inflammation resulting in insulin resistance. Understanding the mechanisms underlying this inflammation would provide valuable insights into the disease and potentially offer new therapeutic targets. Early studies showing that sodium salicylate can reverse the symptoms of type 2 diabetes (1) highlighted roles for inhibitor of kB kinase b (IKKb) and Jun N-terminal kinase (JNK) in this process. JNK can directly phosphorylate Serine307 on insulin receptor substrate 1, thus impairing insulin signaling and mediating obesity-induced insulin resistance (2). IKKb can also phosphorylate insulin receptor substrate 1 (3), and myeloid-specific deletion of IKKb in obese mice protects against insulin resistance (4). In addition, IKKbmediated translocation of nuclear factor-kB into the nucleus

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Section: Endogenous Oils Derived From Visceral Fat Of Mho Metabolicasupporting

confidence: 91%

“…Inc.), and 10 mm polystyrene (PS) particles (Phosphorex Inc. Adipocytes were isolated as described previously (25) and were centrifuged at 2,500g for 1 min to release endogenous oils. Where indicated, a lipid-extraction procedure was performed using the Bligh and Dyer method described previously (26).…”

Section: Reagentsmentioning

confidence: 99%

Endogenous Oils Derived From Human Adipocytes Are Potent Adjuvants That Promote IL-1α–Dependent Inflammation

et al. 2014

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“…However, in the long-term impaired lipid utilization in adipocytes might have detrimental consequences. For instance, enlarged adipocyte size has been correlated with changes in adipocyte function and metabolic disease (39,40). Additionally, FoxO1 is a known regulator of the cellular redox state (41), and sustained inhibition of FoxO1 in insulin resistance might lead to enhanced oxidative stress further contributing to impaired insulin action in the fat cell.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor

González

Flier

Molle

et al. 2011

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

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Insulin resistance is a component of the metabolic syndrome and Type 2 diabetes. It has been recently shown that in liver insulin resistance is not complete. This so-called selective insulin resistance is characterized by defective insulin inhibition of hepatic glucose output while insulin-induced lipogenesis is maintained. How this occurs and whether uncoupled insulin action develops in other tissues is unknown. Here we show in a model of chronic hyperinsulinemia that adipocytes develop selective insulin resistance in which translocation of the GLUT4 glucose transporter to the cell surface is blunted yet nuclear exclusion of the FoxO1 transcription factor is preserved, rendering uncoupled insulin-controlled carbohydrate and lipid metabolisms. We found that in adipocytes FoxO1 nuclear exclusion has a lower half-maximal insulin dose than GLUT4 translocation, and it is because of this inherent greater sensitivity that control of FoxO1 by physiological insulin concentrations is maintained in adipocytes with compromised insulin signaling. Pharmacological and genetic interventions revealed that insulin regulates GLUT4 and FoxO1 through the PI3-kinase isoform p110α, although FoxO1 showed higher sensitivity to p110α activity than GLUT4. Transient down-regulation and overexpression of Akt isoforms in adipocytes demonstrated that insulin-activated PI3-kinase signals to GLUT4 primarily through Akt2 kinase, whereas Akt1 and Akt2 signal to FoxO1. We propose that the lower threshold of insulin activity for FoxO1's nuclear exclusion is in part due to its regulation by both Akt isoforms. Identification of uncoupled insulin action in adipocytes suggests this condition might be a general phenomenon of insulin target tissues contributing to insulin resistance's pathophysiology.

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“…The same metabolic abnormalities can be observed in non-obese NAFLD [61]. Adipocyte size might be implicated in the protection of MHO individuals from the adverse effects of obesity since hypertrophy of both subcutaneous and omental adipocytes was increased in T2D [82] and correlated with the degree of fatty liver and the risk of the progression from hepatic steatosis to fibrosis [83].…”

Section: Adipose Tissue Remodeling: the Metabolically Healthy Vs Metmentioning

confidence: 71%

The color of fat and its central role in the development and progression of metabolic diseases

Gaggini

Carli

Gastaldelli

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Excess caloric intake does not always translate to an expansion of the subcutaneous adipose tissue (SAT) and increase in fat mass. It is now recognized that adipocyte type (white, WAT, or brown, BAT), size (large vs. small) and metabolism are important factors for the development of cardiometabolic diseases. When the subcutaneous adipose tissue is not able to expand in response to increased energy intake the excess substrate is stored as visceral adipose tissue or as ectopic fat in tissues as muscle, liver and pancreas. Moreover, adipocytes become dysfunctional (adiposopathy, or sick fat), adipokines secretion is increased, fat accumulates in ectopic sites like muscle and liver and alters insulin signaling, increasing the demand for insulin secretion. Thus, there are some subjects that despite having normal weight have the metabolic characteristics of the obese (NWMO), while some obese expand their SAT and remain metabolically healthy (MHO). In this paper we have reviewed the recent findings that relate the metabolism of adipose tissue and its composition to metabolic diseases. In particular, we have discussed the possible role of dysfunctional adipocytes and adipose tissue resistance to the antilipolytic effect of insulin on the development of impaired glucose metabolism. Finally we have reviewed the possible role of BAT vs. WAT in the alteration of lipid and glucose metabolism and the recent studies that have tried to stimulate browning in human adipose tissue.

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The Relationship of Omental and Subcutaneous Adipocyte Size to Metabolic Disease in Severe Obesity

Cited by 180 publications

References 46 publications

Endogenous Oils Derived From Human Adipocytes Are Potent Adjuvants That Promote IL-1α–Dependent Inflammation

Endogenous Oils Derived From Human Adipocytes Are Potent Adjuvants That Promote IL-1α–Dependent Inflammation

Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor

The color of fat and its central role in the development and progression of metabolic diseases

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