H19X-encoded microRNAs induced by IL-4 in adipocyte precursors regulate proliferation to facilitate differentiation.

Adipose tissue, an organ critical for systemic energy homeostasis, is influenced by type 2 immunity in its development and function. The type 2 cytokine interleukin (IL)-4 induces the proliferation of bipotential adipocyte precursors (APs) in white fat tissue and primes these cells for differentiation into beige adipocytes, which are specialized for thermogenesis. However, the underlying mechanisms have not yet been comprehensively examined. Here, we identified six microRNA (miRNA) genes upregulated upon IL-4 stimulation in APs, miR-322, miR-503, miR-351, miR-542, miR-450a, and miR-450b; these are encoded in the H19X locus of the genome. Their expression is positively regulated by the transcription factor Klf4, whose expression also increases upon IL-4 stimulation. These miRNAs shared a large set of target genes, of which 381 genes were downregulated in mRNA expression upon IL-4 stimulation and enriched in Wnt signaling pathways. Two genes with downregulated expression, Ccnd1 and Fzd6, were repressed by H19X-encoded miRNAs. Additionally, the Wnt signaling activator LiCl downregulated the expression of this group of miRNAs in APs, indicating that Wnt signaling-related genes and these miRNAs form a double-negative feedback regulatory loop. This miRNA/Wnt feedback regulation modulated the elevated proliferation of APs induced by IL-4 stimulation and contributed to priming them for beige adipocyte differentiation. Moreover, the aberrant expression of these miRNAs attenuates the differentiation of APs into beige adipocytes. Collectively, our results suggest that H19X-encoded miRNAs facilitate the transition of APs from proliferation to differentiation in the IL-4-mediated regulation.

The Influence of Ambient Temperature on Adipose Tissue Homeostasis, Metabolic Diseases and Cancers.

Adipose tissue is a recognized energy storage organ during excessive energy intake and an endocrine and thermoregulator, which interacts with other tissues to regulate systemic metabolism. Adipose tissue dysfunction is observed in most obese mouse models and humans. However, most studies using mouse models were conducted at room temperature (RT), where mice were chronically exposed to mild cold. In this condition, energy use is prioritized for thermogenesis to maintain body temperature in mice. It also leads to the activation of the sympathetic nervous system, followed by the activation of ß-adrenergic signaling. As humans live primarily in their thermoneutral (TN) zone, RT housing for mice limits the interpretation of disease studies from mouse models to humans. Therefore, housing mice in their TN zone (~28-30 °C) can be considered to mimic humans physiologically. However, factors such as temperature ranges and TN pre-acclimatization periods should be examined to obtain reliable results. In this review, we discuss how adipose tissue responds to housing temperature and the outcomes of the TN zone in metabolic disease studies. This review highlights the critical role of TN housing in mouse models for studying adipose tissue function and human metabolic diseases.

Reduction in endoplasmic reticulum stress activates beige adipocytes differentiation and alleviates high fat diet-induced metabolic phenotypes.

Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated. In this study we investigated how ER stress affected beige adipocytes differentiation both in vitro and in vivo. Phosphorylation of eIF2α was transiently decreased in the early phase (day 2), whereas it was induced at the late phase with concomitant induction of C/EBP homologous protein (CHOP) during beige adipocytes differentiation. Forced expression of CHOP inhibited the expression of beige adipocytes markers, including Ucp1, Cox8b, Cidea, Prdm16, and Pgc-1α, following the induction of beige adipocytes differentiation. When ER stress was reduced by the chemical chaperone tauroursodeoxycholic acid (TUDCA), the expression of the beige adipocytes marker uncoupling protein 1 (UCP1) was significantly enhanced in inguinal white adipose tissue (iWAT) and high fat diet (HFD)-induced abnormal metabolic phenotype was improved. In summary, we found that ER stress and the UPR induction were closely involved in beige adipogenesis. These results suggest that modulating ER stress could be a potential therapeutic intervention against metabolic dysfunctions via activation of iWAT browning.

Potential Benefits of Acupuncture and Herbs for Obesity-Related Chronic Inflammation by Adipokines.

The adipose tissue is an organ that stores energy in the form of fats. It also has been known as an endocrine playing an integral role in metabolic homeostasis by secreting various adipokines. In obesity, the adipokine components and secretion patterns are altered toward proinflammation with weight gain, causing low chronic inflammation, which is closely linked to various metabolic diseases. Acupuncture and herbs are used for the management of obesity and its comorbidities, and it has been observed that these therapies affect the amount of expression and concentration of adipokines with improved metabolic phenotypes in both animal and human metabolic diseases. In this review, we discuss the role of adipokines and summarize beneficial effects of the treatments such as electroacupuncture, pharmacopuncture, catgut embedding acupuncture, and single and multiple medicinal herbs on obesity and its relations to adipokine composition. It will provide a new insight for applying adipokines as surrogate markers in complementary and alternative medicine practice.