Gut Microbiota-Derived Short-Chain Fatty Acids Facilitate Microbiota:Host Cross talk and Modulate Obesity and Hypertension.

PURPOSE OF REVIEW: The purpose of this review is to summarize the evidence supporting a role of short-chain fatty acids (SCFAs) as messengers facilitating cross talk between the host and gut microbiota and discuss the effects of altered SCFA signaling in obesity and hypertension. RECENT FINDINGS: Recent evidence suggests there to be a significant contribution of gut microbiota-derived SCFAs to microbe:host communication and host metabolism. SCFA production within the intestine modulates intestinal pH, microbial composition, and intestinal barrier integrity. SCFA signaling through host receptors, such as PPARγ and GPCRs, modulates host health and disease physiology. Alterations in SCFA signaling and downstream effects on inflammation are implicated in the development of obesity and hypertension. SCFAs are crucial components of the holobiont relationship; in the proper environment, they support normal gut, immune, and metabolic function. Dysregulation of microbial SCFA signaling affects downstream host metabolism, with implications in obesity and hypertension.

Soluble Epoxide Hydrolase Inhibition by t-TUCB Promotes Brown Adipogenesis and Reduces Serum Triglycerides in Diet-Induced Obesity.

Brown adipose tissue (BAT) is an important target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH) converts bioactive epoxy fatty acids (EpFAs) into less active diols. sEH inhibitors (sEHI) are beneficial in many chronic diseases by stabilizing EpFAs. However, roles of sEH and sEHI in brown adipogenesis and BAT activity in treating diet-induced obesity (DIO) have not been reported. sEH expression was studied in in vitro models of brown adipogenesis and the fat tissues of DIO mice. The effects of the sEHI, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy-benzoic acid (t-TUCB), were studied in vitro and in the obese mice via mini osmotic pump delivery. sEH expression was increased in brown adipogenesis and the BAT of the DIO mice. t-TUCB promoted brown adipogenesis in vitro. Although t-TCUB did not change body weight, fat pad weight, or glucose and insulin tolerance in the obese mice, it decreased serum triglycerides and increased protein expression of genes important for lipid metabolism in the BAT. Our results suggest that sEH may play a critical role in brown adipogenesis, and sEHI may be beneficial in improving BAT protein expression involved in lipid metabolism. Further studies using the sEHI combined with EpFA generating diets for obesity treatment and prevention are warranted.

Methylparaben and butylparaben alter multipotent mesenchymal stem cell fates towards adipocyte lineage.

Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We previously reported that parabens promoted adipocyte differentiation in vitro and increased adiposity but suppressed serum marker of bone formation in vivo. Here, we investigated the effects of parabens (methylparaben and butylparaben) on modulating cell fate of multipotent stem cell line C3H10T1/2. Both parabens modulated adipogenic, osteogenic, and chondrogenic differentiation of C3H10T1/2 cells in vitro. Butylparaben markedly promoted adipogenic differentiation, but suppressed osteogenic and chondrogenic differentiation whereas methylparaben showed similar but less pronounced effects. Moreover, butylparaben, but not methylparaben, was shown to activate peroxisome proliferator-activated receptor (PPAR) γ whereas neither of the paraben was shown to activate glucocorticoid receptor (GR) responsive reporter in C3H10T1/2 cells. The adipogenic effects of butylparaben were significantly attenuated by PPARγ knockdown, but not by GR knockdown. In contrast, paraben's effects on osteoblast differentiation were affected by both knockdowns. Collectively, the results demonstrate opposing effects of parabens on adipogenic and osteoblastogenic/chondrogenic differentiation of multipotent stem cells. In light of the recent findings that parabens are detected in human placenta and milk, our studies provide rationales to study paraben exposure during early development of life in the future.

Naringenin, a citrus flavanone, enhances browning and brown adipogenesis: Role of peroxisome proliferator-activated receptor gamma.

Identifying functional brown adipose tissue (BAT) has provided new hope for obesity treatment and prevention. Functional BAT includes classical BAT and brown-like adipose tissue converted from white adipose tissue. By promoting thermogenesis (i.e., heat production) via uncoupling protein 1 (UCP1), functional BAT can increase energy expenditure and aid obesity treatment and prevention. Naringenin (NAR) is a flavanone primarily found in citrus fruits. NAR has been reported to decrease body weight, increase energy expenditure in treated mice, and promote browning in human adipocytes. Here, we examined the effects of NAR on 3T3-L1 adipocytes' browning and ß-adrenergic agonist isoproterenol (ISO)-stimulated thermogenic activation and classical murine brown adipogenesis. In addition, we demonstrated the signaling pathways and involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in the process. We found that NAR did not increase Ucp1 mRNA expression at the basal (i.e., non-ISO stimulated) condition. Instead, it enhanced Ucp1 and Pgc-1α up-regulation and thermogenesis under ISO-stimulated conditions in 3T3-L1 adipocytes. NAR promoted protein kinase A (PKA) activation and phosphorylation of p38 MAPK downstream of ISO stimulation and activated PPARγ. Pharmacological inhibition of either PKA or p38 and PPARγ knockdown attenuated Ucp1 up-regulation by NAR. Moreover, NAR promoted brown adipogenesis by increasing lipid accumulation, brown marker expression, and thermogenesis in murine brown adipocytes, which was also attenuated by PPARγ knockdown. Together, our results suggest that NAR may promote the development of functional BAT in part through PPARγ activation. NAR's role in combating human obesity warrants further investigation.

Indomethacin promotes browning and brown adipogenesis in both murine and human fat cells.

Indomethacin (Indo), a nonsteroidal antiinflammatory drug, has been shown to promote murine brown adipogenesis both in vitro and in vivo, possibly due to its peroxisome proliferator-activated receptor gamma (PPARγ)-agonist activities. However, it is unclear whether Indo induces browning of white adipocytes from both murine and human origins or induces human brown adipogenesis. To bridge the gap, this study investigated the effects of increasing concentrations of Indo on murine 3T3-L1, human primary subcutaneous white adipocytes (HPsubQ), and human brown (HBr) adipocytes. The results show that Indo dose-dependently enhanced 3T3-L1 adipocyte differentiation and upregulated both mRNA and protein expression of brown and beige adipocyte markers, while simultaneously suppressing white adipocyte-specific marker mRNA expression. mRNA and protein expression of mitochondrial biogenesis and structural genes were dose-dependently enhanced in Indo treated 3T3-L1 adipocytes. This was accompanied by augmented mitochondrial DNA, enhanced oxygen consumption, proton leak, and maximal and spare respiratory capacity. Dose-dependent transactivation of PPARγ confirmed Indo's PPARγ-agonist activity in 3T3-L1 cells. Knockdown of PPARγ significantly attenuated Indo's activities in selective browning genes, demonstrating PPARγ dependence of these effects. Moreover, Indo enhanced mRNA and protein expression of brown markers in HPsubQ adipocytes. Interestingly, Indo-induced differential effects on individual PPARγ isoforms with significant dose-dependent induction of PPARγ-2 and suppression of PPARγ-1 protein expression. Finally, Indo significantly promoted brown adipogenesis in HBr cells. Taken together, these results demonstrate Indo to be a potent thermogenic compound in both murine and human fat cells and may be explored as a therapeutic agent for obesity treatment and prevention.

Resveratrol liposomes and lipid nanocarriers: Comparison of characteristics and inducing browning of white adipocytes.

Trans-resveratrol (R) has a potential to increase energy expenditure via inducing browning in white adipose tissue. However, its low levels of aqueous solubility, stability, and poor bioavailability limit its application. We have successfully synthesized biocompatible, and biodegradable R encapsulated lipid nanocarriers (R-nano), and R encapsulated liposomes (R-lipo). The mean particle size of R-nano and R-lipo were 140 nm and 110 nm, respectively, and their polydispersity index values were less than 0.2. Nanoencapsulation significantly increased aqueous solubility and enhanced chemical stability of R, especially at 37 °C. R-lipo had higher physical and chemical stability than R-nano while R-nano had more prolonged release than R-lipo. Both R-nano and R-lipo increased cellular R content in 3T3-L1 cells. Both R-nano and R-lipo dose-dependently induced uncoupling protein 1 (UCP1) mRNA expression and decreased white specific marker insulin growth factor binding protein 3 expression under isoproterenol (ISO)-stimulated conditions. At the low dose (5 µM), nanoencapsulated compared to native R enhanced UCP1 and beige marker CD137 expression under ISO-stimulated conditions. Compared to R-nano, R-lipo had better biological activity, possibly due to its higher physical and chemical stability at the room and body temperature. Taken together, our study demonstrates that nanoencapsulation increased R's aqueous solubility and stability, which led to enhanced browning of white adipocytes. Even though both R-lipo and R-nano increased R's browning activities, their differential characteristics need to be considered in obesity treatment.

Parabens inhibit fatty acid amide hydrolase: A potential role in paraben-enhanced 3T3-L1 adipocyte differentiation.

Parabens are a class of small molecules that are regularly used as preservatives in a variety of personal care products. Several parabens, including butylparaben and benzylparaben, have been found to interfere with endocrine signaling and to stimulate adipocyte differentiation. We hypothesized these biological effects could be due to interference with the endocannabinoid system and identified fatty acid amide hydrolase (FAAH) as the direct molecular target of parabens. FAAH inhibition by parabens yields mixed-type and time-independent kinetics. Additionally, structure activity relationships indicate FAAH inhibition is selective for the paraben class of compounds and the more hydrophobic parabens have higher potency. Parabens enhanced 3T3-L1 adipocyte differentiation in a dose dependent fashion, different from two other FAAH inhibitors URB597 and PF622. Moreover, parabens, URB597 and PF622 all failed to enhance AEA-induced differentiation. Furthermore, rimonabant, a cannabinoid receptor 1 (CB1)-selective antagonist, did not attenuate paraben-induced adipocyte differentiation. Thus, adipogenesis mediated by parabens likely occurs through modulation of endocannabinoids, but cell differentiation is independent of direct activation of CB1 by endocannabinoids.