Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway.

The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets.

CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms.

Mice overexpressing the nuclear form of CREBH mainly in the liver (CREBH-Tg) showed suppression of high-fat high-sucrose (HFHS) diet-induced obesity accompanied by an increase in plasma fibroblast growth factor 21 (FGF21) levels. CREBH overexpression induced browning in inguinal white adipose tissue (WAT) and whole-body energy expenditure, which was canceled in Fgf21 mice. Deficiency of FGF21 in CREBH-Tg mice mostly canceled the improvement of obesity, but the suppression of inflammation of epidermal WAT, amelioration of insulin resistance, and improvement of glucose metabolism still sustained.

Transgenic Mice Overexpressing SREBP-1a in Male ob/ob Mice Exhibit Lipodystrophy and Exacerbate Insulin Resistance.

Sterol regulatory element-binding protein (SREBP)-1a is a key transcription factor that activates the expression of genes involved in the synthesis of fatty acids, triglycerides (TGs), and cholesterol. Transgenic mice that overexpress the nuclear form of SREBP-1a under the control of the phosphoenolpyruvate carboxykinase promoter (Tg-1a) were previously shown to display a lipodystrophic phenotype characterized by enlarged and fatty livers, diminished peripheral white adipose tissue (WAT), and insulin resistance. In the current study, we crossed these Tg-1a mice with genetically obese (ob/ob) mice (Tg-1a;ob/ob) and examined change in fat distribution between liver and adipose tissues in severe obesity and mechanism underlying the lipodystrophic phenotype in mice with Tg-1a.

Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice.

Peroxisome proliferator-activated receptor α (PPARα) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlr) mice, a mouse model of atherosclerosis.

Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice.

Aims/introduction: Peroxisome proliferator-activated receptor-α (PPARα) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists.

CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα.

CREB3L3 is involved in fatty acid oxidation and ketogenesis in a mutual manner with PPARα. To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, Creb3l3 mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to Ppara mice.

Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing expression.

Objective: The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by ) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 () expression. However, the intestinal CREBH function remains unknown.

Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system.

cAMP responsive element binding protein 3-like 3 (CREB3L3), a transcription factor expressed in the liver and small intestine, governs fasting-response energy homeostasis. Tissue-specific CREB3L3 knockout mice have not been generated till date. To our knowledge, this is the first study using the one-step CRISPR/Cas9 system to generate CREB3L3 floxed mice and subsequently obtain liver- and small intestine-specific Creb3l3 knockout (LKO and IKO, respectively) mice.

Hepatic CREB3L3 controls whole-body energy homeostasis and improves obesity and diabetes.

Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo.

TFE3 controls lipid metabolism in adipose tissue of male mice by suppressing lipolysis and thermogenesis.

Transcription factor E3 (TFE3) is a transcription factor that binds to E-box motifs and promotes energy metabolism-related genes. We previously reported that TFE3 directly binds to the insulin receptor substrate-2 promoter in the liver, resulting in increased insulin response. However, the role of TFE3 in other tissues remains unclear.

TFE3 inhibits myoblast differentiation in C2C12 cells via down-regulating gene expression of myogenin.

Transcription factor E3 (TFE3) belongs to a basic helix-loop-helix family, and is involved in the biology of osteoclasts, melanocytes and their malignancies. We previously reported the metabolic effects of TFE3 on insulin in the liver and skeletal muscles in animal models. In the present study, we explored a novel role for TFE3 in a skeletal muscle cell line.

Dicer has a crucial role in the early stage of adipocyte differentiation, but not in lipid synthesis, in 3T3-L1 cells.

Dicer is a rate-limiting enzyme for microRNA (miRNA) synthesis. To determine the effects of Dicer on adipogenesis, we performed stage-specific knockdown of Dicer using adenovirus encoding short-hairpin RNAi against Dicer in 3T3-L1 cells. When cells were infected with the adenovirus before induction of adipocyte differentiation, Dicer RNAi suppressed the gene expression of inducers of adipocyte differentiation such as PPARγ, C/EBPα, and FAS in 3T3-L1 cells during adipocyte differentiation.