Hyaluronan Accumulates With High-Fat Feeding and Contributes to Insulin Resistance

Li, Kang; Lantier, Louise; Kennedy, Arion; Bonner, Jeffrey S.; Mayes, Wesley H.; Bracy, Deanna P.; Bookbinder, Louis H.; Hasty, Alyssa H.; Thompson, Curtis B.; Wasserman, David H.

doi:10.2337/db12-1502

Cited by 109 publications

(168 citation statements)

References 46 publications

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“…These genes bind to locally synthesized hyaluronan and, as a complex, have been reported to be involved in inflammatory diseases (40). Levels of hyaluronan, an extracellular matrix component, have been reported to increase in adipose tissue (41) as well as insulin-resistant skeletal muscle in mice with diet-induced obesity (42). Our control littermates are both obese and hyperinsulinemic compared with our experimental mice, which is consistent with altered expression of proinflammatory genes.…”

Section: Resultsmentioning

confidence: 99%

Reducing insulin via conditional partial gene ablation in adults reverses diet‐induced weight gain

et al. 2018

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Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor (Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circulating insulin that are too fine to adversely affect glucose homeostasis nonetheless exert control over adiposity.—Page, M. M., Skovsø, S., Cen, H., Chiu, A. P., Dionne, D. A., Hutchinson, D. F., Lim, G. E., Szabat, M., Flibotte, S., Sinha, S., Nislow, C., Rodrigues, B., Johnson, J. D. Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.

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Section: Resultsmentioning

confidence: 99%

Reducing insulin via conditional partial gene ablation in adults reverses diet‐induced weight gain

et al. 2018

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“…The link between hepatic ECM and architectural structural remodeling with insulin resistance has been studied sparingly (Williams et al, 2015a). In one study, tail-vein injection of HFD-fed mice with a hydrolase for hyaluronan, an ECM component, reduces features of muscle and liver insulin resistance (Kang et al, 2013). Moreover, integrin-α1-subunit-deficient mice ( Itga1 −/− ) fed an HFD display reduced fatty liver content but also severe hepatic insulin resistance, compared to wild-type HFD-fed controls (Williams et al, 2015b).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

Soltis

Kennedy

et al. 2017

Cell Reports

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SUMMARY Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet-induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease.

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“…Physiological, integrinmediated cell-ECM communication is critical not only normal ␤-cell function and indeed survival, as discussed here, but also for insulin action on its target tissues. Pathological modification of the ECM in type 2 diabetes, for example by high-fat diet, hyperglycemia-induced advanced glycation end-products (AGEs), or inflammatory cytokine-induced fibrosis, has thus been shown to participate in the insulin resistance state of insulin-targeted tissues (muscle, adipose tissue, and liver) and could impair ␤-cell function in a similar fashion (4,50,59,107,138,146,147). Deleterious cytokines that are elevated in the circulation of individuals with type 2 diabetes directly affect the expression of proteins of different functional classes including the actin cytoskeleton in ␤-cells (103); perhaps this may also occur in target cells to modulate their insulin sensitivity.…”

Section: Cytoskeleton and Fa Remodeling In Type 2 Diabetes: Parallelsmentioning

confidence: 98%

The skeleton in the closet: actin cytoskeletal remodeling in β-cell function

Arous

Halban

2015

American Journal of Physiology-Endocrinology and Metabolism

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Over the last few decades, biomedical research has considered not only the function of single cells but also the importance of the physical environment within a whole tissue, including cell-cell and cell-extracellular matrix interactions. Cytoskeleton organization and focal adhesions are crucial sensors for cells that enable them to rapidly communicate with the physical extracellular environment in response to extracellular stimuli, ensuring proper function and adaptation. The involvement of the microtubular-microfilamentous cytoskeleton in secretion mechanisms was proposed almost 50 years ago, since when the evolution of ever more sensitive and sophisticated methods in microscopy and in cell and molecular biology have led us to become aware of the importance of cytoskeleton remodeling for cell shape regulation and its crucial link with signaling pathways leading to β-cell function. Emerging evidence suggests that dysfunction of cytoskeletal components or extracellular matrix modification influences a number of disorders through potential actin cytoskeleton disruption that could be involved in the initiation of multiple cellular functions. Perturbation of β-cell actin cytoskeleton remodeling could arise secondarily to islet inflammation and fibrosis, possibly accounting in part for impaired β-cell function in type 2 diabetes. This review focuses on the role of actin remodeling in insulin secretion mechanisms and its close relationship with focal adhesions and myosin II.

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Hyaluronan Accumulates With High-Fat Feeding and Contributes to Insulin Resistance

Cited by 109 publications

References 46 publications

Reducing insulin via conditional partial gene ablation in adults reverses diet‐induced weight gain

Reducing insulin via conditional partial gene ablation in adults reverses diet‐induced weight gain

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

The skeleton in the closet: actin cytoskeletal remodeling in β-cell function

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