Proteomics identifies the developmental regulation of HKDC1 in liver of pigs and mice.

During the perinatal period, unique metabolic adaptations support energetic requirements for rapid growth. To gain insight into perinatal adaptations, quantitative proteomics was performed comparing the livers of Yorkshire pigs at postnatal day 7 and adult. These data revealed differences in the metabolic control of liver function including significant changes in lipid and carbohydrate metabolic pathways. Newborn livers showed an enrichment of proteins in lipid catabolism and gluconeogenesis concomitant with elevated liver carnitine and acylcarnitines levels. Sugar kinases were some of the most dramatically differentially enriched proteins compared with neonatal and adult pigs including galactokinase 1 (Galk1), ketohexokinase (KHK), hexokinase 1 (HK1), and hexokinase 4 (GCK). Interestingly, hexokinase domain containing 1 (HKDC1), a newly identified fifth hexokinase associated with glucose disturbances in pregnant women, was highly enriched in the liver during the prenatal and perinatal periods and continuously declined throughout postnatal development in pigs and mice. These changes were confirmed via Western blot and mRNA expression. These data provide new insights into the developmental and metabolic adaptations in the liver during the transition from the perinatal period to adulthood in multiple mammalian species.

Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges.

The Fibroblast Growth Factor 21 (FGF21) is considered an attractive therapeutic target for obesity and obesity-related disorders due to its beneficial effects in lipid and carbohydrate metabolism. FGF21 response is essential under stressful conditions and its metabolic effects depend on the inducer factor or stress condition. FGF21 seems to be the key signal which communicates and coordinates the metabolic response to reverse different nutritional stresses and restores the metabolic homeostasis. This review is focused on describing individually the FGF21-dependent metabolic response activated by some of the most common nutritional challenges, the signal pathways triggering this response, and the impact of this response on global homeostasis. We consider that this is essential knowledge to identify the potential role of FGF21 in the onset and progression of some of the most prevalent metabolic pathologies and to understand the potential of FGF21 as a target for these diseases. After this review, we conclude that more research is needed to understand the mechanisms underlying the role of FGF21 in macronutrient preference and food intake behavior, but also in ß-klotho regulation and the activity of the fibroblast activation protein (FAP) to uncover its therapeutic potential as a way to increase the FGF21 signaling.

Lyophilized Maqui (Aristotelia chilensis) Berry Induces Browning in the Subcutaneous White Adipose Tissue and Ameliorates the Insulin Resistance in High Fat Diet-Induced Obese Mice.

Maqui (Aristotelia Chilensis) berry features a unique profile of anthocyanidins that includes high amounts of delphinidin-3-O-sambubioside-5-O-glucoside and delphinidin-3-O-sambubioside and has shown positive effects on fasting glucose and insulin levels in humans and murine models of type 2 diabetes and obesity. The molecular mechanisms underlying the impact of maqui on the onset and development of the obese phenotype and insulin resistance was investigated in high fat diet-induced obese mice supplemented with a lyophilized maqui berry. Maqui-dietary supplemented animals showed better insulin response and decreased weight gain but also a differential expression of genes involved in de novo lipogenesis, fatty acid oxidation, multilocular lipid droplet formation and thermogenesis in subcutaneous white adipose tissue (scWAT). These changes correlated with an increased expression of the carbohydrate response element binding protein b (Chrebpb), the sterol regulatory binding protein 1c (Srebp1c) and Cellular repressor of adenovirus early region 1A-stimulated genes 1 (Creg1) and an improvement in the fibroblast growth factor 21 (FGF21) signaling. Our evidence suggests that maqui dietary supplementation activates the induction of fuel storage and thermogenesis characteristic of a brown-like phenotype in scWAT and counteracts the unhealthy metabolic impact of an HFD. This induction constitutes a putative strategy to prevent/treat diet-induced obesity and its associated comorbidities.

(-)-Epigallocatechin 3-Gallate Synthetic Analogues Inhibit Fatty Acid Synthase and Show Anticancer Activity in Triple Negative Breast Cancer.

(-)-Epigallocatechin 3-gallate (EGCG) is a natural polyphenol from green tea with reported anticancer activity and capacity to inhibit the lipogenic enzyme fatty acid synthase (FASN), which is overexpressed in several human carcinomas. To improve the pharmacological profile of EGCG, we previously developed a family of EGCG derivatives and the lead compounds G28, G37 and G56 were characterized in HER2-positive breast cancer cells overexpressing FASN. Here, diesters G28, G37 and G56 and two G28 derivatives, monoesters M1 and M2, were synthesized and assessed in vitro for their cytotoxic, FASN inhibition and apoptotic activities in MDA-MB-231 triple-negative breast cancer (TNBC) cells. All compounds displayed moderate to high cytotoxicity and significantly blocked FASN activity, monoesters M1 and M2 being more potent inhibitors than diesters. Interestingly, G28, M1, and M2 also diminished FASN protein expression levels, but only monoesters M1 and M2 induced apoptosis. Our results indicate that FASN inhibition by such polyphenolic compounds could be a new strategy in TNBC treatment, and highlight the potential anticancer activities of monoesters. Thus, G28, G37, G56, and most importantly M1 and M2, are anticancer candidates (alone or in combination) to be further characterized in vitro and in vivo.

Mediterranean Tomato-Based Sofrito Sauce Improves Fibroblast Growth Factor 21 (FGF21) Signaling in White Adipose Tissue of Obese ZUCKER Rats.

SCOPE: Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Since FGF21 production and signaling are regulated by some bioactive dietary compounds, we analyze the impact of Mediterranean tomato-based sofrito sauce on: (i) the FGF21 expression and signaling in visceral white adipose tissue (vWAT), and (ii) the insulin sensitivity of obese Zucker rats (OZR). METHODS AND RESULTS: OZR are fed with a sofrito-supplemented diet or control diet. Insulin sensitivity and FGF21 signaling are determined. We observed that sofrito is able to improve the responsiveness to both hormones in obese rats. Sofrito-supplemented diet increases FGF21 signaling in vWAT by inducing the expression of the FGF receptors (FGFR1 and FGFR4) that promotes the expression of canonical target genes, like Egr-1, c-Fos and uncoupling protein 1 (Ucp1). CONCLUSIONS: A sofrito-supplemented diet improves insulin and FGF21 sensitivity in OZR, explaining part of sofrito's healthy effects on glucose metabolism. In addition, induction of UCP1 and the unchanged body weight despite the hyperphagic behavior of the sofrito-fed rats suggests that the increase in FGF21 signaling correlates with an increase in energy expenditure (EE). Further studies in humans may help to understand whether sofrito consumption increases the EE in obese individuals.