Adipose tissue: a neglected organ in the response to severe trauma?

Despite the manifold recent efforts to improve patient outcomes, trauma still is a clinical and socioeconomical issue of major relevance especially in younger people. The systemic immune reaction after severe injury is characterized by a strong pro- and anti-inflammatory response. Besides its functions as energy storage depot and organ-protective cushion, adipose tissue regulates vital processes via its secretion products. However, there is little awareness of the important role of adipose tissue in regulating the posttraumatic inflammatory response. In this review, we delineate the local and systemic role of adipose tissue in trauma and outline different aspects of adipose tissue as an immunologically active modifier of inflammation and as an immune target of injured remote organs after severe trauma

THP-1 Macrophages and SGBS Adipocytes – A New Human in vitro Model System of Inflamed Adipose Tissue

Obesity is associated with an accumulation of macrophages in adipose tissue. This inflammation of adipose tissue is a key event in the pathogenesis of several obesity-related disorders, particularly insulin resistance. Here, we summarized existing model systems that mimic the situation of inflamed adipose tissue in vitro, most of them being murine. Importantly, we introduce our newly established human model system which combines the THP-1 monocytic cell line and the preadipocyte cell strain Simpson–Golabi–Behmel syndrome (SGBS). THP-1 cells, which originate from an acute monocytic leukemia, differentiate easily into macrophages in vitro. The human preadipocyte cell strain SGBS was recently introduced as a unique tool to study human fat cell functions. SGBS cells are characterized by a high capacity for adipogenic differentiation. SGBS adipocytes are capable of fat cell-specific metabolic functions such as insulin-stimulated glucose uptake, insulin-stimulated de novo lipogenesis and β-adrenergic-stimulated lipolysis and they secrete typical adipokines including leptin, adiponectin, and RBP4. Applying either macrophage-conditioned medium or a direct co-culture of macrophages and fat cells, our model system can be used to distinguish between paracrine and cell-contact dependent effects. In conclusion, we propose this model as a useful tool to study adipose inflammation in vitro. It represents an inexpensive, highly reproducible human system. The methods described here can be easily extended for usage of primary human macrophages and fat cells

Oncostatin M promotes lipolysis in white adipocytes

Oncostatin M (OSM) is a member of the glycoprotein 130 cytokine family that is involved in chronic inflammation and increased in adipose tissue under obesity and insulin resistance. OSM was shown to inhibit adipogenesis, suppress browning, and contribute to insulin resistance in cultured white adipocytes. In contrast, OSM may have a metabolically favourable role on adipocytes in mouse models of obesity and insulin resistance. However, a putative role of OSM in modulating lipolysis has not been investigated in detail to date. To address this, cultured white adipocytes of mouse or human origin were exposed to 10 or 100 ng/ml of OSM for various time periods. In murine 3T3-L1 cells, OSM stimulation directly activated hormone-sensitive lipase (HSL) and other players of the lipolytic machinery, and dose-dependently increased free fatty acid and glycerol release. In parallel, OSM attenuated insulin-mediated suppression of lipolysis and induced phosphorylation of serine-residues on the insulin receptor substrate-1 (IRS1) protein. Key experiments were verified in a second murine and a human adipocyte cell line. Inhibiton of extracellular signal-regulated kinase (ERK)-1/2 activation, abolished OSM-mediated HSL phosphorylation and lipolysis. In conclusion, OSM signalling directly promotes lipolysis in white adipocytes in an ERK1/2-dependent manner

MiR-107 inhibits CDK6 expression, differentiation, and lipid storage in human adipocytes

MicroRNA-107 (miR-107) plays a regulatory role in obesity and insulin resistance, but the mechanisms of its function in adipocytes have not been elucidated in detail. Here we show that overexpression of miR-107 in pre- and mature human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes attenuates differentiation and lipid accumulation. Our results suggest that miR-107 controls adipocyte differentiation via CDK6 and Notch signaling. CDK6 is a validated target of miR-107 and was downregulated upon miR-107 overexpression. Notch3, a signaling receptor involved in adipocyte differentiation, has been shown to decrease upon CDK6 depletion; Here Notch3 and its target Hes1 were downregulated by miR-107 overexpression. In mature adipocytes, miR-107 induces a triglyceride storage defect by impairing glucose uptake and triglyceride synthesis. To conclude, our data suggests that miR-107 has distinct functional roles in preadipocytes and mature adipocytes; Its elevated expression at these different stages of adipocytes may on one hand dampen adipogenesis, and on the other, promote ectopic fatty acid accumulation and reduced glucose tolerance.Peer reviewe

Differentiating SGBS adipocytes respond to PPARγ stimulation, irisin and BMP7 by functional browning and beige characteristics.

Brown and beige adipocytes are enriched in mitochondria with uncoupling protein-1 (UCP1) to generate heat instead of ATP contributing to healthy energy balance. There are few human cellular models to reveal regulatory networks in adipocyte browning and key targets for enhancing thermogenesis in obesity. The Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte line has been a useful tool to study human adipocyte biology. Here we report that SGBS cells, which are comparable to subcutaneous adipose-derived stem cells, carry an FTO risk allele. Upon sustained PPARγ stimulation or irisin (a myokine released in response to exercise) treatment, SGBS cells differentiated into beige adipocytes exhibiting multilocular lipid droplets, high UCP1 content with induction of typical browning genes (Cidea, Elovl3) and the beige marker Tbx1. The autocrine mediator BMP7 led to moderate browning with the upregulation of the classical brown marker Zic1 instead of Tbx1. Thermogenesis potential resulted from PPARγ stimulation, irisin and BMP7 can be activated in UCP1-dependent and the beige specific, creatine phosphate cycle mediated way. The beige phenotype, maintained under long-term (28 days) conditions, was partially reversed by withdrawal of PPARγ ligand. Thus, SGBS cells can serve as a cellular model for both white and sustainable beige adipocyte differentiation and function

Functional Significance and Predictive Value of MicroRNAs in Pediatric Obesity: Tiny Molecules with Huge Impact?

Obesity is a major health concern. While some children develop comorbidities such as insulin resistance and low-grade systemic inflammation upon weight gain, others stay metabolically healthy. There is an urgent need for clinically relevant markers with prognostic value related to disease development and intervention success. MicroRNAs (miRNAs) are established biomarkers for several disease states. Herein, we give a brief overview of miRNA biogenesis and function and the potential role of circulating miRNA in the context of pediatric obesity

Differentiating SGBS adipocytes respond to PPARγ stimulation, irisin and BMP7 by functional browning and beige characteristics

Brown and beige adipocytes are enriched in mitochondria with uncoupling protein-1 (UCP1) to generate heat instead of ATP contributing to healthy energy balance. There are few human cellular models to reveal regulatory networks in adipocyte browning and key targets for enhancing thermogenesis in obesity. The Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte line has been a useful tool to study human adipocyte biology. Here we report that SGBS cells, which are comparable to subcutaneous adipose-derived stem cells, carry an FTO risk allele. Upon sustained PPARγ stimulation or irisin (a myokine released in response to exercise) treatment, SGBS cells differentiated into beige adipocytes exhibiting multilocular lipid droplets, high UCP1 content with induction of typical browning genes (Cidea, Elovl3) and the beige marker Tbx1. The autocrine mediator BMP7 led to moderate browning with the upregulation of the classical brown marker Zic1 instead of Tbx1. Thermogenesis potential resulted from PPARγ stimulation, irisin and BMP7 can be activated in UCP1-dependent and the beige specific, creatine phosphate cycle mediated way. The beige phenotype, maintained under long-term (28 days) conditions, was partially reversed by withdrawal of PPARγ ligand. Thus, SGBS cells can serve as a cellular model for both white and sustainable beige adipocyte differentiation and function

Thermogenic Activation Downregulates High Mitophagy Rate in Human Masked and Mature Beige Adipocytes

L

MicroRNA-192*impairs adipocyte triglyceride storage

We investigated the expression of miR-192* (miR-192-3p) in the visceral adipose tissue (VAT) of obese subjects and its function in cultured human adipocytes. This miRNA is a 3' arm derived from the same pre-miRNA as miR-192 (miR-192-5p) implicated in type 2 diabetes, liver disease and cancers, and is predicted to target key genes in lipid metabolism. In morbidly obese subjects undergoing bariatric surgery preceded by a very low calorie diet, miR-192* in VAT correlated negatively (r = -0.387; p = 0.046) with serum triglyceride (TG) and positively with high-density lipoprotein (HDL) concentration (r = 0.396; p = 0.041). In a less obese patient cohort, the miRNA correlated negatively with the body mass index (r = -0.537; p = 0.026). To characterize the function of miR-192*, we overexpressed it in cultured adipocytes and analyzed the expression of adipogenic differentiation markers as well as cellular TG content. Reduced TG and expression of the adipocyte marker proteins aP2 (adipocyte protein 2) and perilipin 1 were observed. The function of miR-192* was further investigated by transcriptomic profiling of adipocytes expressing this miRNA, revealing impacts on key lipogenic genes. A number of the mRNA alterations were validated by qPCR. Western analysis confirmed a marked reduction of the lipogenic enzyme SCD (stearoyl coenzyme A desaturase-1), the fatty aldehyde dehydrogenase ALDH3A2 (aldehyde dehydrogenase 3 family member A2) and the high-density lipoprotein receptor SCARB1 (scavenger receptor B, type I). SCD and ALDH3A2 were demonstrated to be direct targets of miR-192*. To conclude, the present data identify miR-192* as a novel controller of adipocyte differentiation and lipid homeostasis. (C) 2016 Elsevier B.V. All rights reserved.Peer reviewe