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This article discusses the role of ceramides, a class of sphingolipids, in atherosclerotic cardiovascular disease (ASCVD). Ceramides are bioactive molecules involved in various cellular processes, including inflammation, apoptosis, and insulin resistance. Recent advances in plasma lipidomics have identified circulating ceramides as risk predictors for ASCVD. Ceramide-based risk scores, such as the Coronary Event Risk Test (CERT) 1 and CERT2, have been developed and validated for primary and secondary ASCVD risk stratification. Lowering ceramide levels through various therapeutic strategies shows promise in improving ASCVD outcomes. Further research is needed to understand the mechanisms by which ceramides contribute to atherosclerosis and to determine the potential benefits of ceramide-lowering interventions. [Extracted from the article]

The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable heterogeneity of the adipose tissue stroma provides a cellular basis to enable adipose tissue plasticity in response to various metabolic stimuli. Regulating mitochondrial function at the cellular level in adipocytes, in adipose progenitor cells (APCs), and in adipose tissue macrophages (ATMs) has a profound impact on adipose homeostasis. Moreover, mitochondria facilitate the cell-to-cell communication within WAT, as well as the crosstalk with other organs, such as the liver, the heart, and the pancreas. A better understanding of mitochondrial regulation in the diverse adipose tissue cell types allows us to develop more specific and efficient approaches to improve adipose function and achieve improvements in overall metabolic health. Regulation of mitochondrial activity in white adipocytes is an essential component of adipose tissue and systemic metabolic homeostasis. Additional cells in adipose tissue (progenitors, endothelial cells, immune cells) are also critically regulated by mitochondrial activity in the respective cells. Intercellular and interorgan exchange of mitochondria is an important new mechanism of information exchange between cells and tissues. A key feature of the regulation of mitochondrial activity in adipose tissue is the choice of the preferred carbon source in the respective cells within adipose tissue, that is, use of carbohydrate through glycolysis versus use of lipids for oxidative phosphorylation. The choice of substrate for energy production exerts a profound impact on the characteristic metabolic features of the various cell types that make up adipose tissue and their impact on tissue and systemic energy homeostasis. [ABSTRACT FROM AUTHOR]

Excess adiposity can induce adverse sequelae in multiple cell types and organ systems. The transition from the lean to the obese state is characterized by fundamental cellular changes at the level of the adipocyte. These changes affect the local microenvironment within the respective adipose tissue but can also affect nonadipose systems. Adipocytes within fat pads respond to chronic nutrient excess through hyperplasia or hypertrophy, which can differentially affect interorgan crosstalk between various adipose depots and other organs. This crosstalk is dependent on the unique ability of the adipocyte to coordinate metabolic adjustments throughout the body and to integrate responses to maintain metabolic homeostasis. These actions occur through the release of free fatty acids and metabolites during times of energy need - a process that is altered in the obese state. In addition, adipocytes release a wide array of signalling molecules, such as sphingolipids, as well as inflammatory and hormonal factors (adipokines) that are critical for interorgan crosstalk. The interactions of adipose tissue with the kidney - referred to as the adipo-renal axis - are important for normal kidney function as well as the response of the kidney to injury. Here, we discuss the mechanistic basis of this interorgan crosstalk, which clearly has great therapeutic potential given the increasing rates of chronic kidney disease secondary to obesity and type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Mutations in mitochondrial genome are one of the most important causes of hearing loss, of these, mitochondrial tRNA (mt-tRNA) genes are the hot spots for mutations associated with deafness. Most recently, a novel mt-tRNAPhe C628T variant has been reported to be associated with non-syndromic and sensorineural hearing loss. To test this association, we characterized the C628T variant using a phylogenetic approach; in addition, we employed the bioinformatics tool to predict the thermodynamic change of the mt-tRNAPhe gene with and without this variant. Intriguingly, the C628T variant was not evolutionary conserved and had little effect on mt-tRNAPhe folding. Moreover, through the application of the pathogenicity scoring system, we classified the C628T variant as a 'neutral polymorphism', suggesting that this variant currently lacked sufficient evident to support as a 'pathogenic' mutation. [ABSTRACT FROM AUTHOR]

Abstract: A series of N-thiazole substituted arylacetamides were designed on the basis of metabolic mechanism of the aminothiazole fragment as glucokinase (GK) activators for the treatment of type 2 diabetes. Instead of introducing a substituent to block the metabolic sensitive C-5 position on the thiazole core directly, a wide variety of C-4 or both C-4 and C-5 substitutions were explored. Compound R-9k bearing an iso-propyl group as the C-4 substituent was found possessing the highest GK activation potency with an EC50 of 0.026μM. This compound significantly increased both glucose uptake and glycogen synthesis in rat primary cultured hepatocytes. Moreover, single oral administration of compound R-9k exerted significant reduction of blood glucose levels in both ICR and ob/ob mice. These promising results indicated that compound R-9k is a potent orally active GK activator, and is warranted for further investigation as a new anti-diabetic treatment. [Copyright &y& Elsevier]

Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide rapidly induced a reduction in leptin. This leptin reduction contributed to the beneficial effects of GLP-1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtailed the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain was observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slowed down weight gain and preserved better glucose tolerance. Mechanistically, a significant reduction in leptin induced a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss, and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance. Article Highlights: Weight loss agents in the glucagon-like peptide 1 receptor and FGF21 group induced a rapid suppression of leptin immediately upon agonist exposure. This leptin suppression significantly contributed to the weight loss. Further leptin suppression with a leptin neutralizing antibody enhanced weight loss and further improved insulin sensitivity. Enhanced leptin reduction leads to further reduction in hepatic steatosis and fibrosis. [ABSTRACT FROM AUTHOR]

Obesity is frequently concomitant with chronic adipose inflammation, although its role in the pathophysiology of obesity remains inconclusive. We previously described that constitutively suppressing adipose inflammation indeed impairs adipose development and leads to profound systemic metabolic disturbances. RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TNFα and IL1β. To avoid developmental issues, we generated a tet-responsive promoter-driven RIDα/β ("TRE-RID") mouse and crossed it to an adiponectinP-rtTA mouse to achieve doxycycline(dox)-inducible, adipocyte-specific expression of this transgene (referred to as fatRID mice). We induced RIDα/β expression with dox-chow diet at 8-weeks of age. Upon induction, RIDα/β is specifically expressed in adipocytes, but not in the liver. LPS-stimulated inflammatory markers, such as TNFα, IL1β and Saa3 are significantly decreased in transgenic mice. Under dox-chow fed conditions, fatRID mice display higher levels of glucose and insulin upon refeeding. FatRID mice exhibit glucose intolerance and insulin resistance. Under obesogenic condition with high-fat-diet (HFD, supplement with dox) feeding, fatRID mice gain less weight, but also display insulin resistance. Moreover, to precondition the mice with inflammation and obesity, mice were pre-fed with HFD without dox for 30 days, and then switched to dox-containing HFD. Under these conditions, fatRID mice exhibit similar body weights, but still display glucose intolerance, insulin resistance, massive fatty liver and reduced adiponectin levels. These metabolic impairments were seen despite the fact that inflammatory pathways (including TNFα and IL1β) are effectively reduced. Combined, suppressing adipose inflammation under either normal or obese conditions promotes insulin resistance, despite beneficial (or minimally no negative) effects on body weight. Disclosure: Q. Zhu: None. P.E. Scherer: None. Funding: National Institutes of Health [ABSTRACT FROM AUTHOR]

Lipolysis leads to the breakdown of stored triglycerides (TAG) to release free fatty acids (FFA) and glycerol which is utilized by energy expenditure pathways to generate energy. Therefore, a decrease in lipolysis augments fat accumulation in adipocytes which promotes weight gain. Conversely, if lipolysis is not complemented by energy expenditure, it leads to FFA induced insulin resistance and type-2 diabetes. Thus, lipolysis is under stringent physiological regulation, although the precise mechanism of the regulation is not known. Deletion of inositol hexakisphosphate kinase-1 (IP6K1), the major inositol pyrophosphate biosynthetic enzyme, protects mice from high fat diet (HFD) induced obesity and insulin resistance. IP6K1-KO mice are lean due to enhanced energy expenditure. Therefore, IP6K1 is a target in obesity and type-2 diabetes. However, the mechanism/s by which IP6K1 regulates adipose tissue lipid metabolism is yet to be understood. Here, we demonstrate that IP6K1-KO mice display enhanced basal lipolysis. IP6K1 modulates lipolysis via its interaction with the lipolytic regulator protein perilipin1 (PLIN1). Furthermore, phosphorylation of IP6K1 at a PKC/PKA motif modulates its interaction with PLIN1 and lipolysis. Thus, IP6K1 is a novel regulator of PLIN1 mediated lipolysis. [ABSTRACT FROM AUTHOR]

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: A series of benzamide derivatives which can simultaneously inhibit glycogen phosphorylase (GP) and activate glucokinase (GK) were prepared and evaluated. The structure–activity relationships (SAR) of these compounds were also presented. Among these, compounds 12, 13l, 13q, and 13v showed moderate activities towards both GK and GP. Compound 13h inhibited hLGP with an IC50 of 8.95μM and activated GK with an EC50 of 1.87μM. The possible binding modes of compounds 12, 13l, 13h, and 13q with GP and GK were also explored by molecular docking simulation. [Copyright &y& Elsevier]

Dermal fibroblasts are an essential population of skin cells. They are not only responsible for synthesis and remodelling of the extracellular matrix of the dermis, but also communicate with other skin cells via autocrine and paracrine interactions. Skin‐associated dermal adipocytes reside below the reticular dermis. Strong lipolysis is observed during the regression of dermal adipocytes. However, the nature of the local intercellular crosstalk in which lipids released by dermal adipocytes affecting the metabolism of adjacent skin fibroblasts has not yet been examined. With the use of a series of novel mouse models that allow us to manipulate adipocytes, we demonstrate that dermal adipocytes can modulate the structure of the dermis through regulating extracellular matrix production in dermal fibroblasts. Fatty acids released by dermal adipocytes are involved in this process. Our observations offer new in vivo insights into the role of dermal adipocyte‐derived lipids in influencing metabolism of adjacent local cells in the skin through a paracrine effect in the microenvironment of the dermal adipocyte. [ABSTRACT FROM AUTHOR]

Enhancing energy expenditure (EE) is an attractive strategy to combat obesity and diabetes. Global deletion of Ip6k1 protects mice from diet-induced obesity (DIO) and insulin resistance, but the tissue-specific mechanism by which IP6K1 regulates body weight is unknown. Here, we have demonstrated that IP6K1 regulates fat accumulation by modulating AMPK-mediated adipocyte energy metabolism. Cold exposure led to downregulation of Ip6k1 in murine inguinal and retroperitoneal white adipose tissue (IWAT and RWAT) depots. Adipocyte-specific deletion of Ip6k1 (AdKO) enhanced thermogenic EE, which protected mice from high-fat diet-induced weight gain at ambient temperature (23°C), but not at thermoneutral temperature (30°C). AdKO-induced increases in thermogenesis also protected mice from cold-induced decreases in body temperature. UCP1, PGC1α, and other markers of browning and thermogenesis were elevated in IWAT and RWAT of AdKO mice. Cold-induced activation of sympathetic signaling was unaltered, whereas AMPK was enhanced, in AdKO IWAT. Moreover, beige adipocytes from AdKO IWAT displayed enhanced browning, which was diminished by AMPK depletion. Furthermore, we determined that IP6 and IP6K1 differentially regulate upstream kinase-mediated AMPK stimulatory phosphorylation in vitro. Finally, treating mildly obese mice with the IP6K inhibitor TNP enhanced thermogenesis and inhibited progression of DIO. Thus, IP6K1 regulates energy metabolism via a mechanism that could potentially be targeted in obesity. [ABSTRACT FROM AUTHOR]

Abstract: Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references. [Copyright &y& Elsevier]

Abstract: A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC50 values of 28.3 and 44.8nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds. [Copyright &y& Elsevier]