Tschimganidine reduces lipid accumulation through AMPK activation and alleviates high-fat diet-induced metabolic diseases.

Obesity increases the risk of mortality and morbidity because it results in hypertension, heart disease, and type 2 diabetes. Therefore, there is an urgent need for pharmacotherapeutic drugs to treat obesity. We performed a screening assay using natural products with anti-adipogenic properties in 3T3-L1 cells and determined that tschimganidine, a terpenoid from the Umbelliferae family, inhibited adipogenesis. To evaluate the anti-obesity effects of tschimganidine in vivo. Mice were fed either a normal chow diet (NFD) or a high-fat chow diet (HFD) with or without tschimganidine for 12 weeks. Treatment with tschimganidine decreased lipid accumulation and adipogenesis, accompanied by reduced expression of adipogenesis and lipid accumulation-related factors. Tschimganidine significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased that of AKT. Depletion of AMPK relieved the reduction in lipid accumulation resulting from tschimganidine treatment. Moreover, tschimganidine administration drastically reduced the weight and size of both gonadal white adipose tissue (WAT) and blood glucose levels in high-fat diet-induced obese mice. We suggest that tschimganidine is a potent antiobesity agent, which impedes adipogenesis and improves glucose homeostasis. Tschimganidine can then be evaluated for clinical application as a therapeutic agent. [BMB Reports 2023; 56(4): 246-251].

A PDE1 inhibitor reduces adipogenesis in mice via regulation of lipolysis and adipogenic cell signaling.

Vinpocetine, a phosphodiesterase (PDE) type-1 inhibitor, increases cAMP and cGMP levels and is currently used for the management of cerebrovascular disorders, such as stroke, cerebral hemorrhage, and cognitive dysfunctions. In this study, we first determined that vinpocetine effectively suppressed adipogenesis and lipid accumulation. However, we questioned which molecular mechanism is involved because the role of PDE in adipogenesis is still controversial. Vinpocetine decreased adipogenic cell signaling, including the phosphorylation of ERK, AKT, JAK2, and STAT3, and adipokine secretion, including IL-6, IL-10, and IFN-α. Interestingly, vinpocetine increased the phosphorylation of HSL, suggesting the induction of the lipolysis pathway. Moreover, vinpocetine increased UCP1 expression via increasing cAMP and PKA phosphorylation. The administration of vinpocetine with a normal-chow diet (NFD) or a high-fat diet (HFD) in mice attenuated body weight gain in mice fed both the NFD and HFD. These effects were larger in the HFD-fed mice, without a difference in food intake. Vinpocetine drastically decreased fat weight and adipocyte cell sizes in gonadal and inguinal white adipose tissues and in the liver in both diet groups. Serum triacylglycerol levels and fasting blood glucose levels were reduced by vinpocetine treatment. This study suggested that vinpocetine prevents adipocyte differentiation through the inhibition of adipogenesis-associated cell signaling in the early stages of adipogenesis. Moreover, upregulating cAMP levels leads to an increase in lipolysis and UCP1 expression and then inhibits lipid accumulation. Therefore, we suggest that vinpocetine could be an effective agent for treating obesity, as well as improving cognition and cardiovascular function in older individuals.

Kahweol inhibits lipid accumulation and induces Glucose-uptake through activation of AMP-activated protein kinase (AMPK).

Weight loss ≥ 5 percent is sufficient to significantly reduce health risks for obese people; therefore, development of novel weight loss compounds with reduced toxicity is urgently required. After screening of natural compounds with antiadipogenesis properties in 3T3-L1 cells, we determined that kahweol, a coffee-specific diterpene, inhibited adipogenesis. Kahweol reduced lipid accumulation and expression levels of adipogenesis and lipid accumulation-related factors. Levels of phosphorylated AKT and phosphorylated JAK2, that induce lipid accumulation, decreased in kahweol-treated cells. Particularly, kahweol treatment significantly increased AMP-activated protein kinase (AMPK) activation. We revealed that depletion of AMPK alleviated reduction in lipid accumulation from kahweol treatment, suggesting that inhibition of lipid accumulation by kahweol is dependent on AMPK activation. We detected more rapid reduction in blood glucose levels in mice administrated kahweol than in control mice. We suggest that kahweol has anti-obesity effects and should be studied further for possible therapeutic applications. [BMB Reports 2017; 50(11): 566-571].

Glucose deprivation triggers protein kinase C-dependent ß-catenin proteasomal degradation.

Autophagy is a conserved process that contributes to cell homeostasis. It is well known that induction mainly occurs in response to nutrient starvation, such as starvation of amino acids and insulin, and its mechanisms have been extensively characterized. However, the mechanisms behind cellular glucose deprivation-induced autophagy are as of now poorly understood. In the present study, we determined a mechanism by which glucose deprivation induced the PKC-dependent proteasomal degradation of ß-catenin, leading to autophagy. Glucose deprivation was shown to cause a sub-G1 transition and enhancement of the LC3-II protein levels, whereas ß-catenin protein underwent degradation in a proteasome-dependent manner. Moreover, the inhibition of GSK3ß was unable to abolish the glucose deprivation-mediated ß-catenin degradation or up-regulation of LC3-II protein levels, which suggested GSK3ß-independent protein degradation. Intriguingly, the inhibition of PKCα using a pharmacological inhibitor and transfection of siRNA for PKCα was observed to effectively block glucose deprivation-induced ß-catenin degradation as well as the increase in LC3-II levels and the accumulation of a sub-G1 population. Together, our results demonstrated a molecular mechanism by which glucose deprivation can induce the GSK3ß-independent protein degradation of ß-catenin, leading to autophagy.

Association of polymorphisms in the vitamin D receptor promoter with idiopathic short stature.

The genetic alterations of vitamin D receptor (VDR) are related with the growth of long bone. There were a lot of reports regarding an association of polymorphisms in the VDR promoter with many disorders, but not with idiopathic short stature (ISS). We investigated the association of them with ISS. A total of 50 subjects, including 29 ISS patients and 21 healthy controls with their heights within the normal range was recruited. We selected two single nucleotide polymorphisms (SNPs) from VDR promoter (rs11568820 at the Cdx-2 binding site upstream of exon 1e and rs4516035 at -1012 upstream of exon 1a) as candidates, respectively. In genotype analysis, the frequency of A/A genotype at the Cdx-2 binding site locus (rs11568820) upstream of exon 1e of VDR was decreased to 6.9% in ISS patients (28.6% in controls) (P = 0.027). The genetic variation at the Cdx-2 binding site of VDR promoter can be a contributing factor of growth of height.

Novel compound heterozygous mutations in the vitamin D receptor gene in a Korean girl with hereditary vitamin D resistant rickets.

Hereditary vitamin D resistant rickets (HVDRR) is a rare genetic disorder caused by a mutation of vitamin D receptor (VDR) gene. A number of cases had been reported in many countries but not in Korea. We examined a three-year old Korean girl who had the typical clinical features of HVDRR including rickets, hypocalcemia, hypophosphatemia, elevated serum calcitriol level and secondary hyperparathyroidism. The girl and her father were both heterozygous for the 719C-to-T(I146T)---> c.437C > T(p.T1461) [corrected] mutation in exon 4, whereas she and her mother were both heterozygous for 754C-to-T (R154C)---> c.472 > T(p.R158C) [corrected] mutation in exon 5 of the VDR gene. In this familial study, we concluded that the girl had compound heterozygous mutations in her VDR gene which caused HVDRR. This is the first report of a unique mutation in the VDR gene in Korea.