scholarly journals Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 991
Author(s):  
Aimo Kannt ◽  
Sridharan Rajagopal ◽  
Mahanandeesha S. Hallur ◽  
Indu Swamy ◽  
Rajendra Kristam ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Recent Work ◽  
Small Molecule ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Binding Modes ◽  
Methyl Group ◽  
X Ray ◽  
Adenosyl Methionine

Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies.

scholarly journals Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation

FEBS Open Bio ◽  
2015 ◽  
Vol 5 (1) ◽  
pp. 557-570 ◽  
Author(s):  
Mikiya Satoh ◽  
Hajime Saburi ◽  
Tomoyuki Tanaka ◽  
Yoshinori Matsuura ◽  
Hisashi Naitow ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Small Molecule ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography ◽  
Multiple Binding

IMPACT OF FAT-FREE ADIPOSE TISSUE ON THE PREVALENCE OF LOW MUSCLE MASS ESTIMATED USING CALF CIRCUMFERENCE IN MIDDLE-AGED AND OLDER ADULTS

2019 ◽  
pp. 1-4
Author(s):  
T. Abe ◽  
S.J. Dankel ◽  
Z.W. Bell ◽  
E. Fujita ◽  
Y. Yaginuma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Muscle Mass ◽  
Predictive Value ◽  
Screening Tool ◽  
Dual Energy ◽  
Fat Cells ◽  
Calf Circumference ◽  
X Ray ◽  
Japanese Adults

Previous studies proposed calf circumference cutoff values for predicting dual-energy X-ray absorptiometry (DXA)-derived low muscle mass. However, DXA-derived appendicular lean mass (aLM) includes non-skeletal muscle components such as the appendicular fat-free component of adipose tissue fat cells (aFFAT). The purpose of this study was to compare the calf circumference method of classification before (Model #1) and after (Model #2) eliminating the influence of FFAT in healthy Japanese adults (50 to 79 years; mean age 70 (SD 7) years). Model 1, and Model 2 for classifying low muscle mass had a sensitivity of 78% and 64%, specificity of 76% and 75%, positive predictive value of 31% and 28%, and negative predictive value of 96% and 93%, respectively. Appendicular fat-free component of adipose tissue has the potential to influence the ability of calf circumference to accurately classify individuals with low muscle mass. Consideration should be made when using this as a screening tool for low muscle mass.

Regulatory effects of N-3 PUFAs on pancreatic β-cells and insulin-sensitive tissues

2021 ◽  
Vol 22 ◽  
Author(s):  
Wen Liu ◽  
Qing Zheng ◽  
Min Zhu ◽  
Xiaohong Liu ◽  
Jingping Liu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Secretion ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Nonalcoholic Fatty Liver ◽  
Wide Range ◽  
Regulatory Effects

: The N-3 polyunsaturated fatty acids (PUFAs) have a wide range of health benefits, including anti-inflammatory effects, improvements in lipids metabolism and promoting insulin secretion, as well as reduction of cancer risk. Numerous studies support that N-3 PUFAs have the potentials to improve many metabolic diseases, such as diabetes, nonalcoholic fatty liver disease and obesity, which are attributable to N-3 PUFAs mediated enhancement of insulin secretion by pancreatic β-cells and improvements in insulin sensitivity and metabolic disorders in peripheral insulin-sensitive tissues such as liver, muscles, and adipose tissue. In this review, we summarized the up-to-date clinical and basic studies on the regulatory effects and molecular mechanisms of N-3 PUFAs mediated benefits on pancreatic β-cells, adipose tissue, liver, and muscles in the context of glucose and/or lipid metabolic disorders. We also discussed the potential factors involved in the inconsistent results from different clinical researches of N-3 PUFAs.

scholarly journals Implications of Skeletal Muscle Extracellular Matrix Remodeling in Metabolic Disorders: Diabetes Perspective

2020 ◽  
Vol 21 (11) ◽  
pp. 3845 ◽  
Author(s):  
Khurshid Ahmad ◽  
Inho Choi ◽  
Yong-Ho Lee
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Matrix Remodeling ◽  
Therapeutic Approaches ◽  
Ecm Remodeling ◽  
Metabolic Dysregulation ◽  
Pathological Conditions ◽  
Insulin Activity

The extracellular matrix (ECM) provides a scaffold for cells, controlling biological processes and providing structural as well as mechanical support to surrounding cells. Disruption of ECM homeostasis results in several pathological conditions. Skeletal muscle ECM is a complex network comprising collagens, proteoglycans, glycoproteins, and elastin. Recent therapeutic approaches targeting ECM remodeling have been extensively deliberated. Various ECM components are typically found to be augmented in the skeletal muscle of obese and/or diabetic humans. Skeletal muscle ECM remodeling is thought to be a feature of the pathogenic milieu allied with metabolic dysregulation, obesity, and eventual diabetes. This narrative review explores the current understanding of key components of skeletal muscle ECM and their specific roles in the regulation of metabolic diseases. Additionally, we discuss muscle-specific integrins and their role in the regulation of insulin sensitivity. A better understanding of the importance of skeletal muscle ECM remodeling, integrin signaling, and other factors that regulate insulin activity may help in the development of novel therapeutics for managing diabetes and other metabolic disorders.

scholarly journals Elucidating the Regulatory Role of Melatonin in Brown, White, and Beige Adipocytes

2019 ◽  
Author(s):  
Ziye Xu ◽  
Wenjing You ◽  
Jiaqi Liu ◽  
Yizhen Wang ◽  
Tizhong Shan
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Body Weight Gain ◽  
Tissue Mass ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Beige Adipocytes

AbstractThe high prevalence of obesity and its associated metabolic diseases has heightened the importance of understanding control of adipose tissue development and energy metabolism. In mammals, 3 types of adipocytes with different characteristics and origins have been identified: white, brown, and beige. Beige and brown adipocytes contain numerous mitochondria and have the capability to burn energy and counteract obesity, while white adipocytes store energy and are closely associated with metabolic disorders and obesity. Thus, regulation of the development and function of different adipocytes is important for controlling energy balance and combating obesity and related metabolic disorders. Melatonin is a neurohormone, which plays multiple roles in regulating inflammation, blood pressure, insulin actions, and energy metabolism. This article summarizes and discusses the role of melatonin in white, beige, and brown adipocytes, especially in affecting adipogenesis, inducing beige formation or white adipose tissue browning, enhancing brown adipose tissue mass and activities, improving anti-inflammatory and antioxidative effects, regulating adipokine secretion, and preventing body weight gain. Based on the current findings, melatonin is a potential therapeutic agent to control energy metabolism, adipogenesis, fat deposition, adiposity, and related metabolic diseases.

Intermuscular adipose tissue-free skeletal muscle mass: estimation by dual-energy X-ray absorptiometry in adults

2004 ◽  
Vol 97 (2) ◽  
pp. 655-660 ◽  
Author(s):  
Jaehee Kim ◽  
Stanley Heshka ◽  
Dympna Gallagher ◽  
Donald P. Kotler ◽  
Laurel Mayer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Prediction Models ◽  
Model Development ◽  
Race Model ◽  
Dual Energy ◽  
Whole Body ◽  
Study Objective ◽  
X Ray ◽  
Intermuscular Adipose Tissue

Skeletal muscle (SM) is a large and physiologically important compartment. Adipose tissue is found interspersed between and within SM groups and is referred to as intermuscular adipose tissue (IMAT). The study objective was to develop prediction models linking appendicular lean soft tissue (ALST) estimates by dual-energy X-ray absorptiometry (DXA) with whole body IMAT-free SM quantified by magnetic resonance imaging. ALST and total-body IMAT-free SM were evaluated in 270 healthy adults [body mass index (BMI) of <35 kg/m2]. The SM prediction models were then validated by the leave-one-out method and by application in a new group of subjects who varied in SM mass [anorexia nervosa (AN), n = 23; recreational athletes, n = 16; patients with acromegaly, n = 7]. ALST alone was highly correlated with whole body IMAT-free SM [ model 1: R2 = 0.96, standard error (SE) = 1.46 kg, P < 0.001]; age ( model 2: R2 = 0.97, SE = 1.38 kg, P < 0.001) and sex and race ( model 3: R2 = 0.97, SE = 1.06 kg, both P < 0.001) added significantly to the prediction models. All three models validated in the athletes and patients with acromegaly but significantly ( P < 0.01–0.001) over-predicted SM in the AN group as a whole. However, model 1 was validated in AN patients with BMIs in the model-development group range ( n = 11; BMI of >16 kg/m2) but not in those with a BMI of <16 kg/m2 ( n = 12). The DXA-based models are accurate for predicting IMAT-free SM in selected populations and thus provide a new opportunity for quantifying SM in physiological and epidemiological investigations.

scholarly journals Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders

2021 ◽  
Vol 18 (2) ◽  
pp. 511
Author(s):  
Kaiser Wani ◽  
Hind AlHarthi ◽  
Amani Alghamdi ◽  
Shaun Sabico ◽  
Nasser M. Al-Daghri
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Nlrp3 Inflammasome Activation ◽  
Specific Inhibitors

NLRP3 inflammasome is one of the multimeric protein complexes of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing pyrin and HIN domain family (PYHIN). When activated, NLRP3 inflammasome triggers the release of pro-inflammatory interleukins (IL)-1β and IL-18, an essential step in innate immune response; however, defective checkpoints in inflammasome activation may lead to autoimmune, autoinflammatory, and metabolic disorders. Among the consequences of NLRP3 inflammasome activation is systemic chronic low-grade inflammation, a cardinal feature of obesity and insulin resistance. Understanding the mechanisms involved in the regulation of NLRP3 inflammasome in adipose tissue may help in the development of specific inhibitors for the treatment and prevention of obesity-mediated metabolic diseases. In this narrative review, the current understanding of NLRP3 inflammasome activation and regulation is highlighted, including its putative roles in adipose tissue dysfunction and insulin resistance. Specific inhibitors of NLRP3 inflammasome activation which can potentially be used to treat metabolic disorders are also discussed.

scholarly journals A Potential Linking between Vitamin D and Adipose Metabolic Disorders

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Zhiguo Miao ◽  
Shan Wang ◽  
Yimin Wang ◽  
Liping Guo ◽  
Jinzhou Zhang ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Energy Metabolism ◽  
Medical Therapy ◽  
Calcium Homeostasis ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Biological Effects ◽  
Vitamin D Supplements ◽  
The Relationship

Vitamin D has been discovered centuries ago, and current studies have focused on the biological effects of vitamin D on adipogenesis. Besides its role in calcium homeostasis and energy metabolism, vitamin D is also involved in the regulation of development and process of metabolic disorders. Adipose tissue is a major storage depot of vitamin D. This review summarized studies on the relationship between vitamin D and adipogenesis and furthermore focuses on adipose metabolic disorders. We reviewed the biological roles and functionalities of vitamin D, the correlation between vitamin D and adipose tissue, the effect of vitamin D on adipogenesis, and adipose metabolic diseases. Vitamin D is associated with adipogenesis, and vitamin D supplements can reduce the burden caused by metabolic diseases. The review provides new insights and basis for medical therapy on adipose metabolic diseases.

scholarly journals Supplemental epilactose prevents metabolic disorders through uncoupling protein-1 induction in the skeletal muscle of mice fed high-fat diets

2015 ◽  
Vol 114 (11) ◽  
pp. 1774-1783 ◽  
Author(s):  
Yuki Murakami ◽  
Teruyo Ojima-Kato ◽  
Wataru Saburi ◽  
Haruhide Mori ◽  
Hirokazu Matsui ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Propionic Acid ◽  
Metabolic Disorders ◽  
Uncoupling Protein ◽  
C2c12 Cells ◽  
High Fat ◽  
Brown Adipose

AbstractObesity is one of the major health problems throughout the world. The present study investigated the preventive effect of epilactose – a rare non-digestible disaccharide – on obesity and metabolic disorders in mice fed high-fat (HF) diets. Feeding with HF diets increased body weight gain, fat pad weight and adipocyte size in mice (P<0·01), and these increases were effectively prevented by the use of supplemental epilactose without influencing food intake (P<0·01). Caecal pools of SCFA such as acetic and propionic acids in mice fed epilactose were higher compared with mice not receiving epilactose. Supplemental epilactose increased the expression of uncoupling protein (UCP)-1, which enhances energy expenditure, to 2-fold in the gastrocnemius muscle (P=0·04) and to 1·3-fold in the brown adipose tissue (P=0·02) in mice fed HF diets. Feeding HF diets induced pro-inflammatory macrophage infiltration into white adipose tissue, as indicated by the increased expression of monocyte chemotactic protein-1, TNF-α and F4/80, and these increases were attenuated by supplemental epilactose. In differentiated myogenic-like C2C12 cells, propionic acid, but not acetic or n-butyric acids, directly enhanced UCP-1 expression by approximately 2-fold (P<0·01). Taken together, these findings indicate that the epilactose-mediated increase in UCP-1 in the skeletal muscle and brown adipose tissue can enhance whole-body energy expenditure, leading to effective prevention of obesity and metabolic disorders in mice fed HF diets. It is suggested that propionic acid – a bacterial metabolite – acts as a mediator to induce UCP-1 expression in skeletal muscles.

scholarly journals Interorgan Metabolic Crosstalk in Human Insulin Resistance

2018 ◽  
Vol 98 (3) ◽  
pp. 1371-1415 ◽  
Author(s):  
Sofiya Gancheva ◽  
Tomas Jelenik ◽  
Elisa Álvarez-Hernández ◽  
Michael Roden
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Short Chain Fatty Acids ◽  
Fatty Acid Esters

Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.

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