Loss of skeletal muscle mass and strength has recently become a hot research topic with the extension of life span and an increasingly sedentary lifestyle in modern society. Maintenance of skeletal muscle mass is considered an essential determinant of muscle strength and function. Myokines are cytokines synthesized and released by myocytes during muscular contractions. They are implicated in autocrine regulation of metabolism in the muscle as well as in the paracrine/endocrine regulation of other tissues and organs including adipose tissue, the liver, and the brain through their receptors. Till date, secretome analysis of human myocyte culture medium has revealed over 600 myokines. In this review article, we summarize our current knowledge of major identified and characterized myokines focusing on their biological activity and function, particularly in muscle mass and function.
Immune cell infiltration of expanding adipose tissue during obesity and its role in insulin resistance has been described and involves chemokines. However, studies so far have focused on a single chemokine or its receptor (especially CCL2 and CCL5) whereas redundant functions of chemokines have been described. The objective of this work was to explore the expression of chemokines in inflamed adipose tissue in obesity. Human and mouse adipocytes were analyzed for expression of chemokines in response to inflammatory signal (TNF-α) using microarrays and gene set enrichment analysis. Gene expression was verified by qRT-PCR. Chemokine protein was determined in culture medium with ELISA. Chemokine expression was investigated in human subcutaneous adipose tissue biopsies and mechanism of chemokine expression was investigated using chemical inhibitors and cellular and animal transgenic models. Chemokine encoding genes were the most responsive genes in TNF-α treated human and mouse adipocytes. mRNA and protein of 34 chemokine genes were induced in a dose-dependent manner in the culture system. Furthermore, expression of those chemokines was elevated in human obese adipose tissue. Finally, chemokine expression was reduced by NF-κB inactivation and elevated by NF-κB activation. Our data indicate that besides CCL2 and CCL5, numerous other chemokines such as CCL19 are expressed by adipocytes under obesity-associated chronic inflammation. Their expression is regulated predominantly by NF-κB. Those chemokines could be involved in the initiation of infiltration of leukocytes into obese adipose tissue.
Ghrelin signaling has major effects on energy and glucose homeostasis, but it is unknown whether ghrelin’s functions are centrally and/or peripherally mediated. The ghrelin receptor, growth hormone secretagogue receptor (GHS-R), is highly expressed in the brain and detectable in some peripheral tissues. To understand the roles of neuronal GHS-R, we generated a mouse line where Ghsr gene is deleted in all neurons using synapsin 1 (Syn1)-Cre driver. Our data showed that neuronal Ghsr deletion abolishes ghrelin-induced spontaneous food intake but has no effect on total energy intake. Remarkably, neuronal Ghsr deletion almost completely prevented diet-induced obesity (DIO) and significantly improved insulin sensitivity. The neuronal Ghsr-deleted mice also showed improved metabolic flexibility, indicative of better adaption to different fuels. In addition, gene expression analysis suggested that hypothalamus and/or midbrain might be the sites that mediate the effects of GHS-R in thermogenesis and physical activity, respectively. Collectively, our results indicate that neuronal GHS-R is a crucial regulator of energy metabolism and a key mediator of DIO. Neuronal Ghsr deletion protects against DIO by regulating energy expenditure, not by energy intake. These novel findings suggest that suppressing central ghrelin signaling may serve as a unique antiobesity strategy.
Efficient delivery of tumor antigens and immunostimulatory adjuvants into lymph nodes is crucial for the maturation and activation of antigen-presenting cells (APCs), which subsequently induce adaptive antitumor immunity. A dissolving microneedle (MN) has been considered as an attractive method for transcutaneous immunization due to its superior ability to deliver vaccines through the stratum corneum in a minimally invasive manner. However, because dissolving MNs are mostly prepared using water-soluble sugars or polymers for their rapid dissolution in intradermal fluid after administration, they are often difficult to formulate with poorly water-soluble vaccine components. Here, we develop amphiphilic triblock copolymer-based dissolving MNs in situ that generate nanomicelles (NMCs) upon their dissolution after cutaneous application, which facilitate the efficient encapsulation of poorly water-soluble Toll-like receptor 7/8 agonist (R848) and the delivery of hydrophilic antigens. The sizes of NMCs range from 30 to 40 nm, which is suitable for the efficient delivery of R848 and antigens to lymph nodes and promotion of cellular uptake by APCs, minimizing systemic exposure of the R848. Application of MNs containing tumor model antigen (OVA) and R848 to the skin of EG7-OVA tumor-bearing mice induced a significant level of antigen-specific humoral and cellular immunity, resulting in significant antitumor activity.
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