Preventive effects of Salvia officinalis leaf extract on insulin resistance and inflammation in a model of high fat diet-induced obesity in mice that responds to rosiglitazone

Background Salvia officinalis (sage) is a native plant to the Mediterranean region and has been used for a long time in traditional medicine for various diseases. We investigated possible anti-diabetic, anti-inflammatory and anti-obesity effects of sage methanol (MetOH) extract in a nutritional mouse model of obesity, inflammation and insulin resistance, as well as its effects on lipolysis and lipogenesis in 3T3-L1 cells. Methods Diet-induced obese (DIO) mice were treated for 5 weeks with sage methanol extract (100 and 400 mg.kg-1/day. bid), or rosiglitazone (3 mg.kg-1/day. bid), as a positive control. Energy expenditure, food intake, body weight, fat mass, liver glycogen and lipid content were evaluated. Blood glucose, and plasma levels of insulin, lipids leptin and pro- and anti-inflammatory cytokines were measured throughout the experiment. The effects of sage MetOH extract on lipolysis and lipogenesis were tested in vitro in 3T3-L1 cells. Results After two weeks of treatment, the lower dose of sage MetOH extract decreased blood glucose and plasma insulin levels during an oral glucose tolerance test (OGTT). An insulin tolerance test (ITT), performed at day 29 confirmed that sage improved insulin sensitivity. Groups treated with low dose sage and rosiglitazone showed very similar effects on OGTT and ITT. Sage also improved HOMA-IR, triglycerides and NEFA. Treatment with the low dose increased the plasma levels of the anti-inflammatory cytokines IL-2, IL-4 and IL-10 and reduced the plasma level of the pro-inflammatory cytokines IL-12, TNF-α, and KC/GRO. The GC analysis revealed the presence of two PPARs agonist in sage MetOH extract. In vitro, the extract reduced in a dose-related manner the accumulation of lipid droplets; however no effect on lipolysis was observed. Conclusions Sage MetOH extract at low dose exhibits similar effects to rosiglitazone. It improves insulin sensitivity, inhibits lipogenesis in adipocytes and reduces inflammation as judged by plasma cytokines. Sage presents an alternative to pharmaceuticals for the treatment of diabetes and associated inflammation

PCR arrays indicate that the expression of extracellular matrix and cell adhesion genes in human adipocytes is regulated by IL-1β (interleukin-1β)

The role of IL-1β in regulating the expression of extracellular matrix (ECM) and cell adhesion genes in human adipocytes has been examined. Adipocytes differentiated in culture were incubated with IL-1β for 4 or 24 h and RNA probed with PCR arrays for 84 ECM and cell adhesion genes. Treatment with IL-1β resulted in changes in the expression at one or both time points of ~50% of the genes probed by the arrays, the majority being down-regulated. Genes whose expression was down-regulated by IL-1β included those encoding several collagen chains and integrin subunits. In contrast, IL-1β induced substantial increases (>10-fold) in the expression of ICAM1, VCAM1, MMP1 and MMP3; the secretion of the encoded proteins was also markedly stimulated. IL-1β has a pervasive effect on the expression of ECM and cell adhesion genes in human adipocytes, consistent with the derangement of tissue structure during inflammation in white fat

IL-1β (interleukin-1β) stimulates the production and release of multiple cytokines and chemokines by human preadipocytes

The effect of IL-1β on cytokine and chemokine production by human preadipocytes has been examined. Preadipocytes were incubated with IL-1β and cytokine and chemokine release measured at 24 h by protein arrays, while the expression of cytokine/chemokine genes was assessed by qPCR at 4 and 24 h. IL-1β stimulated the secretion of multiple cytokines/chemokines, including IL-6, IL-8, IL-10, IL-13, MCP-4, TNFα and IP-10. IL-10 was not released by un-stimulated preadipocytes, while IL-6 exhibited the greatest response to IL-1β (453-fold increase). IL-16 and IL-12p40 did not respond to IL-1β. qPCR demonstrated that IL-1β markedly stimulated CCL3, CSF3 and CXCL10expression at 4 h (>900-fold mRNA increase). A time-course indicated that while CCL13 (encoding MCP-4) exhibited minimal basal expression in preadipocytes, expression increased progressively following differentiation. Human preadipocytes are highly sensitive to IL-1β, the cytokine stimulating a major inflammatory response in these cells similar to that in mature adipocytes

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4

PCR array and protein array studies demonstrate that IL-1β (interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human adipocytes was examined. Adipocytes were incubated with human IL-1β for 4 or 24 h. The expression of a panel of 84 cytokine/chemokine genes was probed using PCR arrays. IL-1β stimulated the expression of >30 cytokine/chemokine genes on the arrays; 15 showed >100-fold increases in mRNA at 4 or 24 h including CSF3, CXCL1, CXCL2, CXCL12 and IL8. CSF3 exhibited a 10,000-fold increase in mRNA at 4 h. ADIPOQ was among the genes whose expression was inhibited. Protein arrays were used to examine the secretion of cytokines/chemokines from adipocytes. IL-1β stimulated the secretion of multiple cytokines/chemokines including MCP-1, IL-8, IP-10, MIP-1α and MCP-4. The most responsive was IP-10, which exhibited a 5,000-fold increase in secretion with IL-1β. IL-1β is likely to play a substantial role in stimulating the inflammatory response in human adipocytes in obesity