Objective Expansion of visceral adipose tissue (VAT) and metabolic inflammation are consequences of obesity and associated with type 2 diabetes (DM). Metabolically activated adipose tissue macrophages (ATMs) undergo qualitative and quantitative changes that influence their inflammatory responses. How these cells contribute to insulin resistance (IR) in humans is not well understood. Cholesterol 25-Hydroxylase

Objective In individuals with mitochondrial disease, respiratory viral infection can result in metabolic decompensation with mitochondrial hepatopathy. Here, we used a mouse model of liver-specific Complex IV deficiency to study hepatic allostasis during respiratory viral infection. Methods Mice with hepatic cytochrome c oxidase deficiency (LivCox10-/-) were infected with aerosolized influenza, A/PR/8

Background and Purpose: Roux-en-Y gastric bypass surgery (RYGB) can achieve long-term remission of type 2 diabetes. However, the specific molecular mechanism through which this occurs has remained largely elusive. Bile acid signaling through the nuclear hormone receptor farnesoid X receptor (FXR) exerts beneficial effects after sleeve gastrectomy (VSG), which has similar effects to RYGB. Therefore

Objective A sustained high fat diet in mice mimics many features of human obesity. We used male and female Non-Swiss albino mice to investigate the impact of short and long-term high-fat diet-(HFD) induced obesity on the peripheral neuromuscular junction (NMJ) and whether obesity-related synaptic structural alterations were reversible after switching obese mice from HFD to standard fat diet (SD). Methods

Objective The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying consequences of lacking GH action. In this study, we used molecular profiling

Objective Orexin (ORX) and melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus are critical regulators of energy homeostasis and thought to differentially contribute to diet-induced obesity. However, it is unclear whether synaptic properties of these cells are altered by obesogenic diet over time. Methods Rats and mice were fed a control chow or palatable high-fat diet (HFD) for

Background ATP-dependent chromatin remodelers are evolutionarily-conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin-remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors. Scope of Review In this review, an overview of the

Objective The metabolic influence of gut microbiota plays a pivotal role in the pathogenesis of cardiometabolic diseases. Antibiotics affect intestinal bacterial diversity and long-term usage has been identified as independent risk factor for atherosclerosis-driven events. Aim of this study was to explore the interaction between gut dysbiosis by antibiotics and metabolic pathways with impact on atherosclerosis

Objectives Decreased muscle mass is a major contributor to age-related morbidity and strategies to improve muscle regeneration during ageing are urgently needed. Our aim was to identify the subset of relevant microRNAs (miRNAs) that partake in critical aspects of muscle cell differentiation, irrespective of computational predictions, genomic clustering or differential expression of the miRNAs. Methods

Objective Understanding the mechanisms that control brown adipose tissue (BAT) mass and functionality is crucial for our understanding of how disruption of energy homeostasis leads to obesity. Bernerdinali Seip Congenital Lipodystrophy (BSCL) type 2 (BSCL2, a.k.a. SEIPIN), a lipodystrophy-associated protein, has been shown not required for brown adipogenesis, but is essential for perinatal BAT development

Objective Acute administration of the main protein component of high-density lipoprotein, apolipoprotein A-I (ApoA-1), improves glucose uptake in skeletal muscle. The molecular mechanisms mediating this are not known, but in muscle cell cultures, ApoA-1 failed to increase glucose uptake when infected with a dominant-negative AMP-activated protein kinase (AMPK) virus. We therefore investigated whether

Objective Glomerular injury is a prominent pathological feature of the diabetic kidney disease (DKD). Constitutively active NADPH oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) that mediates hyperglycemia-induced mesangial cell (MC) fibrotic injury. Nox4 utilizes to exhibit its biological outcome remain exclusive, and the signaling pathways regulate this isoform oxidase are not

Objective: T-box 1 (TBX1) has been identified as a genetic marker of beige adipose tissue. TBX1 is a mesodermal development transcription factor essential for tissue patterning and cell fate determination. However, whether it plays a role in the process of adipose beiging or how it functions in adipose tissue has not been reported. Here, we examined the function of TBX1 in adipose tissue as well as

Background Virtually all eucharyotic cells contain spatially distinct genomes; a single nuclear genome that harbours the vast majority of genes and much smaller genomes found in mitochondria present at thousands of copies per cell. In order to generate a coordinated gene response to various environmental cues, the genomes must communicate with each another. Much of this bi-directional crosstalk relies

Objective As diabetes develops marked reductions of insulin secretion are associated with very modest elevations of glucose. We asked if such glucose changes disrupt beta cell differentiation enough to account for the altered function. Methods Rats were subjected to 90% partial pancreatectomies and those with only mild glucose elevations 4 wk or 10 wk after surgery were found to have major alterations

Background Many metabolites serve as important signaling molecules to adjust cell activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-Coenzyme

Background Metabolic diseases such as obesity are known to be driven by both environmental and genetic factors. Although genome-wide association studies of common variants and their impact in complex traits have provided some biological insight into disease etiology, identified genetic variants have been found to contribute only a small proportion to disease heritability and to map mainly to non-coding

Background Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis and cellular bioenergetics. Increased nucleotide metabolism supports uncontrolled growth of tumors and is a hallmark of cancer. Agents inhibiting synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics to reduce tumor growth, cause DNA

Background Organisms can be primed by metabolic exposures to continue expressing response genes even once the metabolite is no longer available, and can affect the speed and magnitude of responsive gene expression during subsequent exposures. This “metabolic transcriptional memory” can have a profound impact on the survivability of organisms in fluctuating environments. Scope of review Here I present

Background Poly-ADP-ribose polymerases (PARPs) are key mediators of the cellular stress response. Through the consumption of NAD+ they are intimately linked to cellular metabolism. In the nucleus PARP1/ARTD1 is the major NAD+ consuming activity and has a key role in maintaining genomic integrity. Scope of Review In this review, we will discuss how different organelles are linked through NAD+ metabolism

Background One of the fascinating aspects of epigenetic regulation is that it provides means to rapidly adapt to environmental change. This is particularly relevant in the plant kingdom, where most species are sessile and exposed to increasing habitat fluctuations due to global warming. Although the inheritance of epigenetically controlled traits acquired through environmental impact is a matter of

Objective The steep rise in the prevalence of obesity and its related metabolic syndrome has become a major worldwide health concern. Melanocortin peptides from hypothalamic arcuate nucleus (Arc) POMC neurons induce satiety to limit food intake. Consequently, Arc Pomc-deficient mice (ArcPomc-/-) exhibit hyperphagia and obesity. Previous studies have demonstrated that the circulating levels of adiponectin

Objectives In the pathogenesis of type 2 diabetes development of insulin resistance triggers an increase in pancreatic β-cell insulin secretion capacity and β-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of β-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The β-cell factors that normally protect against dedifferentiation remain

Background Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women at reproductive age. While its cardinal manifestations include hyperandrogenism, oligo/anovulation and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder;

Objective Diabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell’s response to an adverse metabolic environment with impaired mitochondrial function remains unclear. Methods Here we report that the oxidoreductase

Objective Histaminergic neurons of the tuberomammillary nucleus (TMN) are wake promoting and contribute to the regulation of energy homeostasis. Evidence indicates that melanocortin 4 receptors (MC4R) are expressed within the TMN. However, whether the melanocortin system influences the activity and function of TMN neurons expressing histidine decarboxylase (HDC), the enzyme required for histamine synthesis

Objective The most common kidney cancer, clear cell Renal Cell Carcinoma (ccRCC) is closely associated with obesity. In fact, the “clear cell” variant of RCC is given this name due to large lipid droplets within the tumor cells. Although it is well appreciated that renal lipid metabolism is altered in ccRCC, the mechanisms and lipids driving this are not well understood. Methods We used a shotgun lipidomics

Objective There remains a great deal of uncertainty over the veracity of measures of the myokine irisin more than seven years after its original description. The unresolved issues include the nature of transcription of the irisin precursor fibronectin type III domain containing 5 (FNDC5) gene across species, the reliability of irisin levels measured with commercial enzyme-linked immunosorbent assays

Objective In mouse models, deficiency of TTC39B (T39) reduces hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39 we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity. Methods

Objectives Lipolysis, hydrolysis of triacylglycerides to fatty acids, in adipocytes is tightly regulated, poorly understood and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. Here we set out to identify genetic regulators of lipolysis and elucidate molecular mechanisms of effect. Methods Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated

Objective Regulation of food intake and energy balance depends on a group of hypothalamic neurons that release anorexigenic melanocortins encoded by the Pomc gene. Although the physiological importance of central melanocortins is well appreciated, the genetic program that defines the functional identity of melanocortin neurons and assures high levels of hypothalamic Pomc expression is only beginning

Objectives Nutrient sensing by hypothalamic neurons is critical for the regulation of food intake and energy expenditure. We aimed to identify long- and medium-chain fatty acid species transported into the brain, their effects on energy balance and mechanisms by which they regulate activity of hypothalamic neurons. Methods Simultaneous blood and cerebrospinal fluid (CSF) sampling was undertaken in

Objective It is well established that the liver specific miR-122, a bona fide tumor suppressor, plays critical role in lipid homeostasis. However, its role, if any, in amino acid metabolism has not been explored. Since glutamine is a critical energy and anaplerotic source for mammalian cells, we assessed glutamine metabolism in the control (WT) and miR-122 knockout mice (KO) by SIRM (Stable Isotope

Background The diminished glucose lowering effect of insulin in obesity, denoted “insulin resistance”, is associated with glucose intolerance, type 2 diabetes and other serious maladies. Many thousands of publications on the topic have suggested dozens of hypotheses on the molecular and cellular disruptions that contribute to the syndrome. Yet there is still deep uncertainty on the mechanisms of its

BACKGROUND Leptin acts via its receptor, LepRb, on specialized neurons in the brain to modulate energy balance and glucose homeostasis. LepRb→STAT3 signaling plays a crucial role in leptin action, but LepRb also mediates an additional as-yet-unidentified signal (Signal 2) that is important for leptin action. Signal 2 requires LepRb regions in addition to those required for JAK2 activation but operates

OBJECTIVE A widely recognized metabolic side effect of glucocorticoid (GC) therapy is steroid-induced diabetes mellitus (DM). However, studies on the molecular basis of GC-induced pancreatic beta cell dysfunction in human beta cells are lacking. The significance of non-coding RNAs in various cellular processes is emerging. In this study, we aimed to show the direct negative impact of GC on beta cell

BACKGROUND The microbiota in the human gut are an important component of normal physiology that has co-evolved from the earliest multicellular organisms. Therefore, it is unsurprising that there is intimate crosstalk between the microbial world in the gut and the host. Genome regulation through microbiota-host interactions not only affects the host's immunity, but also metabolic health and resilience

OBJECTIVE An organism's metabolic phenotype is primarily affected by its genotype, its lifestyle, and the nutritional composition of its food supply. In addition, it is now clear from studies in many different species that ancestral environments can also modulate metabolism in at least one to two generations of offspring. METHODS We limit ourselves here to paternal effects in mammals, primarily focusing

OBJECTIVE Among obesity-associated metabolic diseases, non-alcoholic fatty liver disease (NAFLD) represents an increasing public health issue due to its emerging association with atherogenic dyslipidemia and cardiovascular diseases (CVDs). The lower prevalence of NAFLD in pre-menopausal women compared with men or post-menopausal women led us to hypothesize that the female-inherent ability to counteract

OBJECTIVE Post-bariatric surgery hypoglycemia (PBH) is defined as the presence of neuroglycopenic symptoms accompanied by postprandial hypoglycemia in bariatric surgery patients. Recent clinical studies using continuous glucose monitoring (CGM) technology revealed that PBH is more frequently observed in vertical sleeve gastrectomy (VSG) patients than previously recognized. PBH cannot be alleviated

Objective Estrogen receptor-α (ERα) is a nuclear receptor family member thought to substantially contribute to the metabolic regulation of skeletal muscle. However, previous mouse models utilized to assess the necessity of ERα signaling in skeletal muscle are confounded by altered developmental programming and/or influenced by secondary effects, making it difficult to assign a causal role for ERα.

OBJECTIVE Type 2 diabetes (T2D) is a complex disease characterized by pancreatic islet dysfunction, insulin resistance, and disruption of blood glucose levels. Genome-wide association studies (GWAS) have identified > 400 independent signals that encode genetic predisposition. More than 90% of associated single-nucleotide polymorphisms (SNPs) localize to non-coding regions and are enriched in chromatin-defined

BACKGROUND Cancer cell metabolism can be characterised by adaptive metabolic alterations, which support abnormal proliferative cell growth with high energetic demand. De novo nucleotide biosynthesis is essential for providing nucleotides for RNA and DNA synthesis, and drugs targeting this biosynthetic pathway have proven to be effective anticancer therapeutics. Nevertheless, cancers are often able

OBJECTIVE Bone morphogenetic protein 4 (BMP4) adeno-associated viral vectors of serotype 8 (AAV8) gene therapy targeting the liver prevents the development of obesity in initially lean mice by browning the large subcutaneous white adipose tissue (WAT) and enhancing energy expenditure. Here, we examine whether this approach could also reduce established obesity. METHODS Dietary-induced obese C57BL6/N