The Role of Uncoupling Protein 3 in Human Physiology

Obesity is simply understood as an imbalance between energy intake and expenditure in favor of weight accretion. However, the human biological interface between food consumption and energy dissipation results in broad individual differences in eating behavior, physical activity, and efficiency of fuel storage and metabolism. In particular, the basal metabolic rate, which accounts for the greatest portion of overall energy expenditure, can vary almost twofold among individuals. Classically, three major biochemical systems are believed to contribute to basal thermogenesis: futile cycles, Na+/K+ATPase activity, and mitochondrial proton leak. The latter is the most important quantitative contributor and can explain up to 50% of the basal metabolic rate (1). The molecular basis of mitochondrial proton leak is unclear, despite its importance in the understanding of energy balance and its potential as a therapeutic target for obesity treatment. The article by Hesselink and colleagues in this issue of the JCI (2) addresses whether uncoupling protein 3 contributes to mitochondrial proton leak in human skeletal muscle

New options for the treatment of obesity and type 2 diabetes mellitus (narrative review)

AbstractModerate weight loss (>5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1–2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes

Proinflammatory cytokine production and insulin sensitivity regulated by overexpression of resistin in 3T3-L1 adipocytes

Resistin is secreted from adipocytes, and high circulating levels have been associated with obesity and insulin resistance. To investigate whether resistin could exert autocrine effects in adipocytes, we expressed resistin gene in 3T3-L1 fibroblasts using a lentiviral vector, and selected several stably-transduced cell lines under blasticidin selection. We observed that 3T3-L1 adipocytes expressing resistin have a decreased gene expression for related transcriptional factors (CCAAT/enhancer binding protein α(C/EBPα) , peroxisome proliferator-activated receptor gamma (PPARγ), and adipocyte lipid binding protein (ALBP/aP2) which is one of target genes for the PPARγ during adipocyte differentiation,. Overexpression of resistin increased the levels of three proinflammatory cytokines, tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), which play important roles for insulin resistance, glucose and lipid metabolisms during adipogenesis. Furthermore, overexpressing resistin in adipocytes inhibits glucose transport 4 (GLUT4) activity and its gene expression, reducing insulin's ability for glucose uptake by 30 %. In conclusion, resistin overexpression in stably transduced 3T3-L1 cells resulted in: 1) Attenuation of programmed gene expression responsible for adipogenesis; 2) Increase in expression of proinflammatory cytokines; 3) Decrease in insulin responsiveness of the glucose transport system. These data suggest a new role for resistin as an autocrine/paracrine factor affecting inflammation and insulin sensitivity in adipose tissue

The Expression of TNFα by Human Muscle: Relationship to Insulin Resistance

TNFα is overexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. To more closely link TNF expression with whole body insulin action, we examined the expression of TNF by muscle, which is responsible for the majority of glucose uptake in vivo. Using RT-PCR, TNF was detected in human heart, in skeletal muscle from humans and rats, and in cultured human myocytes. Using competitive RT-PCR, TNF was quantitated in the muscle biopsy specimens from 15 subjects whose insulin sensitivity had been characterized using the glucose clamp technique. TNF expression in the insulin resistant subjects and the diabetic patients was fourfold higher than in the insulin sensitive subjects, and there was a significant inverse linear relationship between maximal glucose disposal rate and muscle TNF (r = -0.60, P \u3c 0.02). In nine subjects, muscle cells from vastus lateralis muscle biopsies were placed into tissue culture for 4 wk, and induced to differentiate into myotubes. TNF was secreted into the medium from these cells, and cells from diabetic patients expressed threefold more TNF than cells from nondiabetic subjects. Thus, TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects. These data suggest another mechanism by which TNF may play an important role in human insulin resistance

Lipoprotein Lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS

<p>Abstract</p> <p>Background</p> <p>Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), ~75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all <it>P </it>< .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (<it>LPL</it>) gene variants: D9N (rs1801177) and S447X (rs328).</p> <p>Findings</p> <p>Mixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (<it>P </it>= .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; <it>P </it>= .04).</p> <p>Conclusions</p> <p>This was the first study this kind to show an association between <it>LPL </it>and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern.</p

A clustering analysis of lipoprotein diameters in the metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>The presence of smaller low-density lipoproteins (LDL) has been associated with atherosclerosis risk, and the insulin resistance (IR) underlying the metabolic syndrome (MetS). In addition, some research has supported the association of very low-, low- and high-density lipoprotein (VLDL HDL) particle diameters with components of the metabolic syndrome (MetS), although this has been the focus of less research. We aimed to explore the relationship of VLDL, LDL and HDL diameters to MetS and its features, and by clustering individuals by their diameters of VLDL, LDL and HDL particles, to capture information across all three fractions of lipoprotein into a unified phenotype.</p> <p>Methods</p> <p>We used nuclear magnetic resonance spectroscopy measurements on fasting plasma samples from a general population sample of 1,036 adults (mean ± SD, 48.8 ± 16.2 y of age). Using latent class analysis, the sample was grouped by the diameter of their fasting lipoproteins, and mixed effects models tested whether the distribution of MetS components varied across the groups.</p> <p>Results</p> <p>Eight discrete groups were identified. Two groups (N = 251) were enriched with individuals meeting criteria for the MetS, and were characterized by the smallest LDL/HDL diameters. One of those two groups, one was additionally distinguished by large VLDL, and had significantly higher blood pressure, fasting glucose, triglycerides, and waist circumference (WC; <it>P </it>< .001). However, large VLDL, in the absence of small LDL and HDL particles, did not associate with MetS features. These associations held after additionally controlling for VLDL, LDL and HDL particle concentrations.</p> <p>Conclusions</p> <p>While small LDL diameters remain associated with IR and the MetS, the occurrence of these in conjunction with a shift to overall larger VLDL diameter may identify those with the highest fasting glucose, TG and WC within the MetS. If replicated, the association of this phenotype with more severe IR-features indicated that it may contribute to identifying of those most at risk for incident type II diabetes and cardiometabolic disease.</p

Ten Years In: Implementing Strategic Approaches to Cyberspace

This book represents a look beyond theories and analogies to examine the challenges of strategy implementation. In the essays that follow, practitioners who are building cyberspace forces at-scale join scholars who study power and force in this new domain to collectively offer a unique perspective on the evolution and future of cyber strategy and operations.https://digital-commons.usnwc.edu/usnwc-newport-papers/1044/thumbnail.jp