Cold-inducible lncRNA266 promotes browning and the thermogenic program in white adipose tissue.

Cold-induced nonshivering thermogenesis has contributed to the improvement of several metabolic syndromes caused by obesity. Several long noncoding RNAs (lncRNAs) have been shown to play a role in brown fat biogenesis and thermogenesis. Here we show that the lncRNA lnc266 is induced by cold exposure in inguinal white adipose tissue (iWAT). In vitro functional studies reveal that lnc266 promotes brown adipocyte differentiation and thermogenic gene expression. At room temperature, lnc266 has no effects on white fat browning and systemic energy consumption. However, in a cold environment, lnc266 promotes white fat browning and thermogenic gene expression in obese mice. Moreover, lnc266 increases core body temperature and reduces body weight gain. Mechanistically, lnc266 does not directly regulate Ucp1 expression. Instead, lnc266 sponges miR-16-1-3p and thus abolishes the repression of miR-16-1-3p on Ucp1 expression. As a result, lnc266 promotes preadipocyte differentiation toward brown-like adipocytes and stimulates thermogenic gene expression. Overall, lnc266 is a cold-inducible lncRNA in iWAT, with a key role in white fat browning and the thermogenic program.

FGF21 impedes peripheral myelin development by stimulating p38 MAPK/c-Jun axis.

Fibroblast growth factor 21 (FGF21) as a metabolic stress hormone, is mainly secreted by the liver. In addition to its well-defined roles in energy homeostasis, FGF21 has been shown to promote remyelination after injury in the central nervous system. In the current study, we sought to examine the potential roles of FGF21 in the peripheral nervous system (PNS) myelination. In the PNS myelin development, Fgf21 expression was reversely correlated with myelin gene expression. In cultured primary Schwann cells (SCs), the application of recombinant FGF21 greatly attenuates myelination-associated gene expression, including Oct6, Krox20, Mbp, Mpz, and Pmp22. Accordingly, the injection of FGF21 into neonatal rats markedly mitigates the myelination in sciatic nerves. On the contrary, the infusion of the anti-FGF21 antibody accelerates the myelination. Mechanistically, both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) were stimulated by FGF21 in SCs and sciatic nerves. Following experiments including pharmaceutical intervention and gene manipulation revealed that the p38 MAPK/c-Jun axis, rather than ERK, is targeted by FGF21 for mediating its repression on myelination in SCs. Taken together, our data provide a new aspect of FGF21 by acting as a negative regulator for the myelin development process in the PNS via activation of p38 MAPK/c-Jun.

Achyranthes bidentata polypeptide protects dopaminergic neurons from apoptosis in Parkinson's disease models both in vitro and in vivo.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a neurodegenerative disorder closely associated with dopaminergic neuron loss. It is well documented that Achyranthes bidentata polypeptides (ABPP) are potent neuroprotective agents in several kinds of neurons. Therefore, we proposed that ABPP might play a beneficial role against PD by protecting dopaminergic neurons from apoptosis. EXPERIMENTAL APPROACH: SH-SY5Y cells and primary rat dopaminergic neurons were pretreated with ABPP fraction k (ABPPk), a purified fraction of ABPP, and then the cells were exposed to 1-methyl-4-phenylpyridinium iodide (MPP+ ) to induce apoptosis. Cell viability, LDH activity, a Tunel assay and protein levels of Bcl-2 and Bax were analysed. In an in vivo PD model induced by MPTP, ABPPk was intranasally delivered to mice. Behavioural tests, immunohistochemistry, immunostaining, Nissl staining, qRT-PCR and Western blot were employed to evaluate the potential effects of ABPPk on PD in mice. KEY RESULTS: The application of ABPPk markedly enhanced the viability of SH-SY5Y cells and primary dopaminergic neurons treated with neurotoxic agent MPP+ . In an in vivo MPTP-induced PD model, ABPPk significantly improved behavioural performances and prevented tyrosine hydroxylase loss in the substantia nigra pars compacta and striatum. Furthermore, we showed that MPTP-induced astrocyte and microglia activation were largely attenuated by ABPPk, leading to low levels of neuroinflammation and a downregulation of the apoptotic signalling pathway. CONCLUSION AND IMPLICATIONS: Taken together, our data show that ABPPk protects dopaminergic neurons from apoptosis, suggesting that ABPPk might be an effective intervention for treating the neuron loss associated with disorders such as PD.

Salsalate Activates Skeletal Muscle Thermogenesis and Protects Mice from High-Fat Diet Induced Metabolic Dysfunction.

Salsalate plays beneficial roles for ameliorating hyperglycemia and dyslipidemia in type 2 diabetes patients, but the underlying mechanisms are still poorly understood. In this study, by administering salsalate to mice fed with high fat diet and examining how salsalate rectifies metabolic dysfunction in these obese mice, we found that salsalate stimulated body temperature and attenuated body weight gain without affecting food intake. Our results showed that salsalate application decreased lipid accumulation in liver and epididymal white adipose tissue (eWAT), inhibited hepatic gluconeogenesis and improved insulin signaling transduction in eWAT. In addition, salsalate increased the expression of genes related to glucose and fatty acid transport and oxidation in skeletal muscle. Our results also showed that expression of genes in mitochondrial uncoupling and mitochondrial electron transport are strengthened by salsalate. Moreover, sarcolipin (Sln) and sarcoplasmic reticulum Ca2+ ATPase 2 (Serca2) in skeletal muscle were enhanced in salsalate-treated mice. Together, our data suggest that the beneficial metabolic effects of salsalate may depend, at least in part, on skeletal muscle thermogenesis via activation of mitochondrial uncoupling and the axis of Sln/Serca2a.

Salidroside improves glucose homeostasis in obese mice by repressing inflammation in white adipose tissues and improving leptin sensitivity in hypothalamus.

Salidroside is a functionally versatile natural compound from the perennial flowering plant Rhodiola rosea L. Here, we examined obese mice treated with salidroside at the dosage of 50 mg/kg/day for 48 days. Mice treated with salidroside showed slightly decreased food intake, body weight and hepatic triglyceride content. Importantly, salidroside treatment significantly improved glucose and insulin tolerance. It also increased insulin singling in both liver and epididymal white adipose tissue (eWAT). In addition, salidroside markedly ameliorated hyperglycemia in treated mice, which is likely due to the suppression of gluconeogenesis by salidroside as the protein levels of a gluconeogenic enzyme G6Pase and a co-activator PGC-1α were all markedly decreased. Further analysis revealed that adipogenesis in eWAT was significantly decreased in salidroside treated mice. The infiltration of macrophages in eWAT and the productions of pro-inflammatory cytokines were also markedly suppressed by salidroside. Furthermore, the leptin signal transduction in hypothalamus was improved by salidroside. Taken together, these euglycemic effects of salidroside may due to repression of adipogenesis and inflammation in eWAT and stimulation of leptin signal transduction in hypothalamus. Thus, salidroside might be used as an effective anti-diabetic agent.