Curcumin Prevents High Fat Diet Induced Insulin Resistance and Obesity via Attenuating Lipogenesis in Liver and Inflammatory Pathway in Adipocytes

Background: Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages. Methodology and Principal Findings: We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue. Conclusions and Significance: We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence o

Short‐term semaglutide treatment improves FGF21 responsiveness in primary hepatocytes isolated from high fat diet challenged mice

Abstract Metabolic functions of GLP‐1 and its analogues have been extensively investigated. In addition to acting as an incretin and reducing body weight, we and others have suggested the existence of GLP‐1/fibroblast growth factor 21 (FGF21) axis in which liver mediates certain functions of GLP‐1 receptor agonists. In a more recent study, we found with surprise that four‐week treatment with liraglutide but not semaglutide stimulated hepatic FGF21 expression in HFD‐challenged mice. We wondered whether semaglutide can also improve FGF21 sensitivity or responsiveness and hence triggers the feedback loop in attenuating its stimulation on hepatic FGF21 expression after a long‐term treatment. Here, we assessed effect of daily semaglutide treatment in HFD‐fed mice for 7 days. HFD challenge attenuated effect of FGF21 treatment on its downstream events in mouse primary hepatocytes, which can be restored by 7‐day semaglutide treatment. In mouse liver, 7‐day semaglutide treatment stimulated FGF21 as well as genes that encode its receptor (FGFR1) and the obligatory co‐receptor (KLB), and a battery of genes that are involved in lipid homeostasis. In epididymal fat tissue, expressions of a battery genes including Klb affected by HFD challenge were reversed by 7‐day semaglutide treatment. We suggest that semaglutide treatment improves FGF21 sensitivity which is attenuated by HFD challenge

The developmental Wnt signaling pathway effector β-catenin/TCF mediates hepatic functions of the sex hormone estradiol in regulating lipid metabolism.

The bipartite transcription factor β-catenin (β-cat)/T cell factor (TCF), formed by free β-cat and a given TCF family member, serves as the effector of the developmental Wnt signaling cascade. β-cat/TCFs also serve as effectors of certain peptide hormones or growth factors during adulthood. We reported that liver-specific expression of dominant-negative Transcription factor 7 like 2 (TCF7L2DN) led to impaired glucose disposal. Here we show that, in this LTCFDN transgenic mouse model, serum and hepatic lipid contents were elevated in male but not in female mice. In hepatocytes, TCF7L2DN adenovirus infection led to stimulated expression of genes that encode lipogenic transcription factors and lipogenic enzymes, while estradiol (E2) treatment attenuated the stimulation, associated with Wnt-target gene activation. Mechanistically, this E2-mediated activation can be attributed to elevated β-cat Ser675 phosphorylation and TCF expression. In wild-type female mice, ovariectomy (OVX) plus high-fat diet (HFD) challenge impaired glucose disposal and insulin tolerance, associated with increased hepatic lipogenic transcription factor sterol regulatory element-binding protein 1-c (SREBP-1c) expression. In wild-type mice with OVX, E2 reconstitution attenuated HFD-induced metabolic defects. Some of the attenuation effects, including insulin intolerance, elevated liver-weight gain, and hepatic SREBP-1c expression, were not affected by E2 reconstitution in HFD-fed LTCFDN mice with OVX. Finally, the effects of E2 in hepatocytes on β-cat/TCF activation can be attenuated by the G-protein-coupled estrogen receptor (GPER) antagonist G15. Our study thus expanded the scope of functions of the Wnt pathway effector β-cat/TCF, as it can also mediate hepatic functions of E2 during adulthood. This study also enriches our mechanistic understanding of gender differences in the risk and pathophysiology of metabolic diseases

The <i>miR-214-5p</i>/Lactoferrin/<i>miR-224-5p</i>/<i>ADAM17</i> Axis Is Involved in Goat Mammary Epithelial Cells’ Immune Regulation

Lactoferrin (LF) is believed to be an important active protein in goat milk, which plays an anti-inflammatory role. Although LF has been reported to be associated with body health, its exact underlying mechanism remains unclear. Here, we aimed to elucidate the mechanism of this anti-inflammatory effect of LF in vitro. We first identified that miR-214-5p inhibited the expression of LF mRNA and protein in cells through the 3′UTR of LF mRNA. We next identified the alterations in miRNA following LF overexpression in goat mammary epithelial cells (GEMCs). Overexpression of LF significantly increased (p miR-224-5p expression. We further revealed that transcriptional activation of ADAM17, TNF-α, IL-1β, and IL-6 was efficiently decreased (p miR-224-5p mimic. Conversely, knockdown of miR-224-5p increased (p ADAM17, TNF-α, IL-1β, and IL-6 expression. Additionally, TNF-α, IL-1β, and IL-6 expression levels were dramatically decreased in GMECs after administration of siADAM17. Herein, we indicate that the miR-214-5p/LF/miR-224-5p/ADAM17 axis is involved in the immune regulation of GEMCs