Key Metabolic Tissues Research Articles

Identification and Characterization of Sebaceous Gland Atrophy-Sparing DGAT1 Inhibitors

Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.

Identification of novel 11β-HSD1 inhibitors by combined ligand- and structure-based virtual screening

11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to cortisol in a NADPH dependent manner. Overexpression of 11β-HSD1 in key metabolic tissues is related to the development of type 2 diabetes, obesity, hypertension and metabolic syndrome. Using crystal structures of human 11β-HSD1 in complex with inhibitors as source of structural information, a combined ligand and structure-based virtual screening approach was implemented to identify novel 11β-HSD1 inhibitors. A selected group of compounds was identified in silico and further evaluated in cell-based assays for cytotoxicity and 11β-HSD1 mediated cortisol production inhibitory capacity. The expression of 11β-HSD1 and 11β-HSD2 in human LS14 adipocytes was assessed during differentiation. Biological evaluation of 39 compounds in adipocytes and steroids quantification by HPLC-MS/MS identify 4 compounds that exhibit 11β-HSD1 mediated cortisol production inhibitory activity with potencies in the micromolar range. Two compounds showed to be selective for the 11β-HSD1 reductase activity and over 11β-HSD2 isoform, and thus represent novel leads for the development of more active derivatives with higher efficacies targeting intracellular cortisol levels in type 2 diabetes and metabolic syndrome.

N−3 polyunsaturated fatty acids modulate metabolism of insulin-sensitive tissues: implication for the prevention of type 2 diabetes

Obesity is frequently associated with the development of type 2 diabetes which is firstly characterized by a defect in the response of key metabolic tissues to insulin (insulin resistance). The imbalance in fatty composition of the diet, a low-grade inflammatory state have been described to be involved in the initiation or the amplification of the molecular events involved in this process. The concept of a specific nutritional intervention has emerged as a promising tool against metabolic disorders associated with obesity. In this context, many investigations were conducted to evaluate the potential beneficial impacts of n-3 polyunsaturated fatty acids (n-3 PUFA). The aim of the present review was to summarize the current knowledge about the role of docosahexanoic acid (DHA, 22:6n-3) and eicosapentanoic acid (EPA, 20:5n-3) on key metabolic organs. Only studies aiming to understand the mechanism of actions were selected. The analysis of randomized clinical trial about n-3 PUFA was not considered here. The effects of n-3 PUFA were analyzed in the adipose tissue, the liver, skeletal muscle and the pancreas in the context of obesity and lipid oversupply. Furthermore, in line with recent findings about the role of the modulation of gut microbiota in obesity-related disorders, we summarized the recent findings about the possible link between n-3 PUFA and change in microbiota composition.

Obesity Activates a Program of Lysosomal-Dependent Lipid Metabolism in Adipose Tissue Macrophages Independently of Classic Activation

Obesity activates a complex systemic immune response that includes the recruitment of macrophages and other immune cells to key metabolic tissues. Current models postulate that obesity and excess lipids classically activate macrophages, polarizing them toward an M1 (inflammatory) state. Little is known about noninflammatory functions ofadipose tissue macrophages (ATMs). Here, we show that the expansion of adipose tissue (AT) across models of obesity induces a program of lysosome biogenesis in ATMs and is associated with lipid catabolism but not a classic inflammatory phenotype. This program is induced by factors produced by AT and is tightly coupled to lipid accumulation by ATMs. Inhibition of ATM lysosome function impairs lipid metabolism and increases lipid content in ATMs and reduces whole AT lipolysis. These data argue that ATMs contribute quantitatively to the development of obesity-induced inflammation but also serve an important role in lipid trafficking independent of their inflammatory phenotype.

The immune cells in adipose tissue

Although the pathological role of the immune system in several metabolic disorders, including type 1 diabetes mellitus (T1DM) and Addison's disease, has long been recognized and studied, only in the last decade has it become apparent that the immune system plays a broad and more subtle role in local and systemic metabolism. It is now apparent that the immune system monitors and responds to specific metabolic cues in both pathologic and non-pathologic settings through a set of processes dubbed immunometabolism. Expansion of adipose tissue mass, activation of lipolysis, eating a high fat diet and even non-shivering thermogenesis all lead to the recruitment and activation of immune cells in key metabolic tissues. The responses are complex and not completely defined, and indeed, as is typical of rapidly evolving research areas, there are some conflicting reports, especially related to the metabolic consequences of manipulation of immune function. However, what is clear is the consensus that metabolic processes, especially obesity and obesity-related complications, activate both the innate and adaptive arms of the immune system. Canonical immune processes consist of discrete steps: surveillance, recognition, effector action and resolution. Over the last decade evidence for each part of the immune response has been found at the intersection of the immune system with metabolism. Although evidence for immune surveillance and modulation of metabolism has been found in the liver, muscle, hypothalamus and pancreas, immune cell function has been most intensively studied and best understood in adipose tissue where studies continue to provide insights into the intersection of the metabolic and immune systems. Here we review the modulation of immune cell populations in adipose tissue and discuss regulatory processes implicated in controlling the interface between metabolism and immunologic function.

Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.

Metformin relieves oxidative stress and leads to differential modulation of function in key metabolic tissues

Metformin reduces hyperglycemia and hyperlipidemia in people with diabetes. We hypothesized that metformin alters a circulating redox state, thereby ameliorating dysregulation of metabolism in multiple tissues. The acute effects of metformin on redox state and tissue function were assessed in primary mouse hepatocytes, human adipocytes, and INS‐1 β‐cells. Metformin increased the NAD+ to NADH ratio in hepatocytes, implying an alteration in redox state. In neither adipocytes nor hepatocytes did metformin have an effect on basal production of reactive oxygen species (ROS), but metformin tended to decrease tert‐butyl‐hydroperoxide‐induced ROS production. A similar pattern was observed on lipid peroxidation in adipocytes. Interestingly, metformin inhibited both basal and forskolin‐induced lipolysis. However, metformin had no effect on basal or glucose‐stimulated insulin secretion in INS‐1 cells. These results suggest that metformin acutely altered the cellular redox state, which may explain its ability to yield various tissue‐specific effects and deliver pleotropic benefits.

Adenosine Nucleotide Biosynthesis and AMPK Regulate Adult Life Span and Mediate the Longevity Benefit of Caloric Restriction in Flies

A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed life span extension. Remarkably, this simple change in dietalso blocked the prolongevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult life span; provide a mechanistic link between cellular anabolism and energy sensing pathways; and indicate that dietary adenine manipulations might alter metabolism to influence animal lifespan.

Inactivation of MARK4, an AMP-activated Protein Kinase (AMPK)-related Kinase, Leads to Insulin Hypersensitivity and Resistance to Diet-induced Obesity

MARK4, also known as Par-1d/MarkL1, is a member of the AMP-activated protein kinase (AMPK)-related family of kinases, which are implicated in the regulation of dynamic biological functions, including glucose and energy homeostasis. However, the physiological function of MARK4 in mammals remains elusive. Here, we investigated a role for MARK4 in regulating energy homeostasis by generating mice with targeted inactivation of the mark4 gene. We show that MARK4 deficiency in mice caused hyperphagia, hyperactivity, and hypermetabolism, leading to protection from diet-induced obesity and its related metabolic complications through up-regulation of brown fat activity. Consequently, MARK4 deficiency mitigated insulin resistance associated with diet-induced obesity by dramatically enhancing insulin-stimulated AKT phosphorylation in major metabolic tissues. Ablation of MARK4 also significantly improved glucose homeostasis by up-regulating the activity and expression of AMPK kinase in key metabolic tissues. Taken together, these data identify a key role of MARK4 in energy metabolism, implicating the kinase as a novel drug target for the treatment of obesity and type 2 diabetes.

New Onset Diabetes and Its Incidence in Severe COVID 19 Disease A Single Centre Study From Kashmir

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes coronavirus disease 2019 (COVID-19), was first reported in Wuhan, China, in December 2019 and has spread worldwide. SARS-CoV-2 is a positivestranded RNA virus that is enclosed by a protein containing lipid bilayer with a single-stranded RNA genome; SARS-CoV-2 has 82% homology with human SARS-CoV, which causes severe acute respiratory syndrome.SARS-CoV-2, virus binds to angiotensinconverting enzyme 2 (ACE2) receptors, which are expressed in key metabolic organs and tissues, including pancreatic beta cells, adipose tissue, the small intestine, and the kidneys. Thus, it is believed that SARS-CoV-2 may cause pleiotropic alterations of glucose metabolism that could complicate the pathophysiology of pre-existing diabetes or lead to new mechanisms of disease. Many studies have made observations that provide support for the hypothesis of a potential diabetogenic effect of Covid-19; in addition it is well-recognized that stress response associated with severe illness have diabetogenic effect. However, whether the alterations of glucose metabolism that occur with a sudden onset in severe COVIOD-19 persist or remit when the infection resolves is unclear. How frequent is the phenomenon of newonset diabetes, and is it classic type 1 or type 2 diabetes or a new type of diabetes. Key words: COVID 19; Prediabetes; Diabetes; Pneumonia.

Akt signaling-associated metabolic effects of dietary gold nanoparticles in Drosophila

Gold nanoparticles (AuNPs) are often used as vehicles to deliver drugs or biomolecules, due to their mild effect on cell survival and proliferation. However, little is known about their effect on cellular metabolism. Here we examine the in vivo effect of AuNPs on metabolism using Drosophila as a model. Drosophila and vertebrates possess similar basic metabolic functions, and a highly conserved PI3K/Akt/mTOR signaling pathway plays a central role in the regulation of energy metabolism in both organisms. We show that dietary AuNPs enter the fat body, a key metabolic tissue in Drosophila larvae. Significantly, larvae fed with AuNP show increased lipid levels without triggering stress responses. In addition, activities of the PI3K/Akt/mTOR signaling pathway and fatty acids synthesis are increased in these larvae. This study thus reveals a novel function of AuNPs in influencing animal metabolism and suggests its potential therapeutic applications for metabolic disorders.

Myostatin inhibition improves hyperglycemia and hyperphagia in lipodystrophic mice

Background Skeletal muscle is a key peripheral metabolic tissue: Muscle is responsible for most insulin-stimulated glucose uptake, and muscle insulin resistance is the first defect detectable in the development of type 2 diabetes. Recent studies show that muscle mass is inversely correlated with insulin resistance in humans. The growth factor myostatin (MSTN) is a negative regulator of skeletal muscle size. Mstn KO mice or mice expressing a dominant negative activin type receptor type IIB (Acrv2B) specifically in muscle (Muscle-DN mice) have increased muscle mass, reduced adipose mass and improved insulin sensitivity. The improvements in insulin sensitivity could be due to the direct effects of the loss of MSTN in muscle or to the secondary effects of reduced adiposity or both. Our hypothesis is that MSTN inhibition specifically in the muscle can improve hyperglycemia in diabetic mice independent of changes in adiposity. To test this hypothesis, we inhibited MSTN signaling in a diabetic model of generalized lipodystrophy (A-ZIP/F-1 mouse model) to analyze its effects on glucose metabolism separate from effects on adipose mass. The A-ZIP/F-1 fatless mouse is a model of lipodystrophy characterized by the lack of white adipose tissue, diabetes, ectopic lipid accumulation and hyperphagia.

ChemInform Abstract: Lipin 1 in Lipid Metabolism

AbstractReview: 22 refs.

Momordica charantia extract, a herbal remedy for type 2 diabetes, contains a specific 11β-hydroxysteroid dehydrogenase type 1 inhibitor

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the intracellular regeneration of active cortisol from inert cortisone in key metabolic tissues, thus regulating ligand access to glucocorticoid receptors. There is strong evidence that increased adipose 11β-HSD1 activity may be an important aetiological factor in the current obesity and diabetes type 2 epidemics. Hence, inhibition of 11β-HSD1 has emerged as a promising anti-diabetic strategy, a concept that is largely supported by numerous studies in rodent models as well as limited clinical data with prototype inhibitors. Momordica charantia (also known as bitter melon, bitter gourd or karela) is traditionally used for treatment of diabetes in Asia, South America, the Caribbean, and East Africa. In the present study, we show that M. charantia extract capsules contain at least one ingredient with selective 11β-HSD1 inhibitory activity. The finding constitutes an interesting additional explanation for the well-documented anti-diabetic and hypoglycaemic effects of M. charantia.

A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans

The cannabinoid CB1 receptor is a well-known player in energy homeostasis and its specific antagonism has been used in clinical practice for the treatment of obesity. The G protein-coupled receptor GPR55 has been recently proposed as a new cannabinoid receptor and, by contrast, its pharmacology is still enigmatic and its physiological role is largely unexplored, with no reports investigating its putative role in metabolism. Thus, we aim to investigate in rats the presence, distribution and putative physiological role of GPR55 in a key metabolic tissue, the endocrine pancreas. We found high Gpr55 mRNA content in pancreatic islets and considerable protein distribution in insulin-secreting β-cells. Activation of GPR55 by the agonist O-1602 increased calcium transients (P<0.01) and insulin secretion (P<0.001) stimulated by glucose. This latter effect was blunted in Gpr55 KO mice suggesting that O-1602 is acting, at least in part, through GPR55. Indeed, acute in vivo experiments showed that GPR55 activation increases glucose tolerance (P<0.05) and plasma insulin levels (P<0.05), suggesting an in vivo physiological relevance of GPR55 systemic stimulation. Taken together, these results reveal the expression of GPR55 receptors in the endocrine pancreas as well as its function at stimulus-secretion coupling of insulin secretion, suggesting a role in glucose homeostasis. In this context, it may also represent a new target for consideration in the management of type 2 diabetes and related diseases.

Genetic tracing of Nav1.8‐expressing vagal afferents in the mouse

Nav1.8 is a tetrodotoxin-resistant sodium channel present in large subsets of peripheral sensory neurons, including both spinal and vagal afferents. In spinal afferents, Nav1.8 plays a key role in signaling different types of pain. Little is known, however, about the exact identity and role of Nav1.8-expressing vagal neurons. Here we generated mice with restricted expression of tdTomato fluorescent protein in all Nav1.8-expressing afferent neurons. As a result, intense fluorescence was visible in the cell bodies, central relays, and sensory endings of these neurons, revealing the full extent of their innervation sites in thoracic and abdominal viscera. For instance, vagal and spinal Nav1.8-expressing endings were seen clearly within the gastrointestinal mucosa and myenteric plexus, respectively. In the gastrointestinal muscle wall, labeled endings included a small subset of vagal tension receptors but not any stretch receptors. We also examined the detailed innervation of key metabolic tissues such as liver and pancreas and evaluated the anatomical relationship of Nav1.8-expressing vagal afferents with select enteroendocrine cells (i.e., ghrelin, glucagon, GLP-1). Specifically, our data revealed the presence of Nav1.8-expressing vagal afferents in several metabolic tissues and varying degrees of proximity between Nav1.8-expressing mucosal afferents and enteroendocrine cells, including apparent neuroendocrine apposition. In summary, this study demonstrates the power and versatility of the Cre-LoxP technology to trace identified visceral afferents, and our data suggest a previously unrecognized role for Nav1.8-expressing vagal neurons in gastrointestinal functions.

Lipin 1 in Lipid Metabolism

The gene encoding lipin 1 was identified with a positional cloning approach that localized the causative mutation in fatty liver dystrophic (fld) mice, a mouse model of lipodystrophy. The fld mouse lacks normal adipose tissue in the body, and displays metabolic dysregulation such as obesity, insulin resistance, and hypertriglyceridemia. Lipin 1 is abundantly expressed in key metabolic tissues, including adipose tissue, skeletal muscle, and liver. In the cytosol, lipin 1 acts as an Mg²⁺-dependent phosphatidate phosphatase type-1 (PAP1), catalyzing a key step in the synthesis of glycerolipids. In the nucleus, lipin 1 acts as a transcriptional coactivator through its direct interaction with peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and PPARα. Through two distinct functions in the nucleus and cytosol, lipin 1 modulates lipid metabolism and glucose homeostasis. Here we will discuss recent developments in our understanding of the role of lipin 1 in lipid metabolism.

Homeorhetic Adaptation During the Pregnancy to Lactation Transition: Role of Solute-Linked Transporter Genes in Key Metabolic Tissues.

Homeorhetic Adaptation During the Pregnancy to Lactation Transition: Role of Solute-Linked Transporter Genes in Key Metabolic Tissues.

Homeorhetic Adaptation During the Pregnancy to Lactation Transition: A Comparative Transcriptome Analysis of Key Metabolic Tissues Using a Rat Model.

Homeorhetic Adaptation During the Pregnancy to Lactation Transition: A Comparative Transcriptome Analysis of Key Metabolic Tissues Using a Rat Model.

11β-Hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of type 2 diabetes

Importance of the field: The prevalence of obesity and type 2 diabetes is rising and reaching pandemic proportions. For this reason, identification of novel therapeutic targets is urgently needed.Areas covered in this review: The endoluminal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes glucocorticoid activation in key metabolic tissues including skeletal muscle, liver and adipose tissue, and is strongly implicated in the pathogenesis of obesity, type 2 diabetes and the metabolic syndrome. Selective 11β-HSD1 inhibitors limit local glucocorticoid availability and improve insulin sensitivity, glucose tolerance, lipid profiles and atherosclerosis. To date, there is a paucity of clinical studies using selective 11β-HSD1 inhibitors; however, early indications show that these compounds have great therapeutic potential.What the reader will gain: We present a comprehensive overview of the background to the development of selective 11β-HSD1 inhibitors, the preclinical data supporting 11β-HSD1 as a therapeutic target, and the current status of clinical trials of these agents.Take home message: Selective 11β-HSD1 inhibitors have the potential to improve insulin sensitivity and may ultimately add to the treatment options available for patients with type 2 diabetes. However, further clinical studies are urgently required.