Abstract
Although coffee consumption has been historically associated with negative health outcomes, recent evidence suggests a lower risk of metabolic syndrome, obesity and diabetes among regular coffee drinkers. Among the plethora of minor organic compounds assessed as potential mediators of coffee health benefits, trigonelline and its pyrolysis product N-methylpyridinium (NMP) were preliminary shown to promote glucose uptake and exert anti-adipogenic properties. Against this background, we aimed at characterizing the effects of trigonelline and NMP in inflamed and dysfunctional human adipocytes. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with NMP or, for comparison, trigonelline, for 5 h before stimulation with tumor necrosis factor (TNF)-α. NMP at concentrations as low as 1 µmol/L reduced the stimulated expression of several pro-inflammatory mediators, including C-C Motif chemokine ligand (CCL)-2, C-X-C Motif chemokine ligand (CXCL)-10, and intercellular adhesion Molecule (ICAM)-1, but left the induction of prostaglandin G/H synthase (PTGS)2, interleukin (IL)-1β, and colony stimulating factor (CSF)1 unaffected. Furthermore, NMP restored the downregulated expression of adiponectin (ADIPOQ). These effects were functionally associated with downregulation of the adhesion of monocytes to inflamed adipocytes. Under the same conditions, NMP also reversed the TNF-α-mediated suppression of insulin-stimulated Ser473 Akt phosphorylation and attenuated the induction of TNF-α-stimulated lipolysis restoring cell fat content. In an attempt to preliminarily explore the underlying mechanisms of its action, we show that NMP restores the expression of the master regulator of adipocyte differentiation peroxisome proliferator-activated receptor (PPAR)γ and downregulates activation of the pro-inflammatory mitogen-activated protein jun N-terminal kinase (JNK). In conclusion, NMP reduces adipose dysfunction in pro-inflammatory activated adipocytes. These data suggest that bioactive NMP in coffee may improve the inflammatory and dysmetabolic milieu associated with obesity.
Highlights
The seriousness of the global epidemic of obesity and type 2 diabetes (T2D), collectively referred to as “diabesity”, can no longer be questioned [1]
Fully differentiated Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were incubated with increasing concentrations of NMP or TRIGO for 5 h before being challenged, or not, with Tumor necrosis factor (TNF)-α for a further 18 h
In an attempt to elucidate the molecular mechanisms through which NMP affects adipocyte physiology under adipogenic pro-inflammatory conditions, we preliminarily investigated the ability of NMP to interact with key molecular switches in adipocyte biology by performing a predictive computational analysis using a molecular docking approach [24]
Summary
The seriousness of the global epidemic of obesity and type 2 diabetes (T2D), collectively referred to as “diabesity”, can no longer be questioned [1]. Updated projections estimate a sixfold increase in the number of adults with obesity in the 40 years, while the number of individuals with diabetes seems destined to reach 642 million by 2040 [2]. Since “diabesity” significantly increases the risk of serious cardiovascular sequelae [3], the consequent huge health burden has prompted the search for new preventive or therapeutic strategies to relieve metabolic dysfunctions in obese diabetic patients. Tumor necrosis factor (TNF)-α is a cytokine secreted by both adipocytes and immune cells within obese WAT [7]. Compared with adipose tissue in lean subjects, TNF-α expression is many times higher in obese subjects [8,9] in correlation with hyperinsulinemia [10]. In an animal model of diet-induced obesity, inflammation drove the expression of the leukocyte adhesion molecule intercellular adhesion molecule (ICAM)-1, which accelerated the adipose homing of monocytes, thereby perpetuating both adipose and vascular inflammation [13,14]
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