[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.

/pdf/inflammatory-mechanisms-in-obesity-4zcumnwrzk.pdf

Inflammatory Mechanisms in Obesity

EVOLUTION: Of Mice . . .

The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.3.763

Sodium/Calcium Exchange: Its Physiological Implications

NF-κB, inflammation, and metabolic disease.

Time for primary review 24 days.

Animals have been used by humans for centuries to understand their own biology. In cardiovascular research, animal models have allowed the study of cardiovascular disease in the early stages, as well as the investigation of the mechanisms of the pathogenesis of cardiovascular disease and the effects of drug intervention. The aim of these studies is to provide clear concepts for selected investigations in humans. An ideal animal model for any cardiovascular disease in humans should have five characteristics: (i) mimic the human disease, (ii) allow studies in chronic, stable disease, (iii) produce symptoms which are predictable and controllable, (iv) satisfy economical, technical and animal welfare considerations, and (v) allow measurement of relevant cardiac, biochemical and haemodynamic parameters.

The use of rats as animal models is rational from the economic viewpoint and many techniques have been developed to measure relevant functional parameters. However, there is often insufficient consideration as to whether the other criteria, especially the mimicry of human disease, are satisfied with the choice of rat models of cardiovascular disease. Three examples illustrate the problems. Firstly, cardiovascular diseases such as hypertension and heart failure in humans are usually slowly developing with wide-ranging neurohumoral adaptations in contrast to the acute onset of symptoms in many surgical or drug-induced rat models of these important diseases. Secondly, cardiovascular disease is uncommon in young humans but markedly increases with age [1]yet most models of hypertension and heart failure only use young adult rats. Animal models of ageing have been recently reviewed [2]. Thirdly, the development of atherosclerosis is very unusual in most strains of rats, even in the presence of sustained high blood lipid levels, in contrast to humans where atherosclerosis is common and an important risk factor in hypertension and heart failure.

Although this review … 

* Corresponding author. Tel.: +64 (9) 373 7599 ext. 6418; Fax: +64 (9) 373 7556.

/pdf/rat-models-of-hypertension-cardiac-hypertrophy-and-failure-31gf392ido.pdf

Rat models of hypertension, cardiac hypertrophy and failure.

The prevalence of metabolic syndrome including central obesity, insulin resistance, impaired glucose tolerance, hypertension, and dyslipidemia is increasing. Development of adequate therapy for metabolic syndrome requires an animal model that mimics the human disease state. Therefore, we have characterized the metabolic, cardiovascular, hepatic, renal, and pancreatic changes in male Wistar rats (8-9 weeks old) fed on a high-carbohydrate, high-fat diet including condensed milk (39.5%), beef tallow (20%), and fructose (17.5%) together with 25% fructose in drinking water; control rats were fed a cornstarch diet. During 16 weeks on this diet, rats showed progressive increases in body weight, energy intake, abdominal fat deposition, and abdominal circumference along with impaired glucose tolerance, dyslipidemia, hyperinsulinemia, and increased plasma leptin and malondialdehyde concentrations. Cardiovascular signs included increased systolic blood pressure and endothelial dysfunction together with inflammation, fibrosis, hypertrophy, increased stiffness, and delayed repolarization in the left ventricle of the heart. The liver showed increased wet weight, fat deposition, inflammation, and fibrosis with increased plasma activity of liver enzymes. The kidneys showed inflammation and fibrosis, whereas the pancreas showed increased islet size. In comparison with other models of diabetes and obesity, this diet-induced model more closely mimics the changes observed in human metabolic syndrome.

High-carbohydrate, high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats

Omega-3 fatty acids and metabolic syndrome: Effects and emerging mechanisms of action

Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet-induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat-fed male rodent.

/pdf/rodent-models-for-metabolic-syndrome-research-bxs3946q73.pdf

Rodent Models for Metabolic Syndrome Research

Survival of multicellular organisms depends on their ability to fight infection, metabolize nutrients, and store energy for times of need. Unsurprisingly, therefore, immunoregulatory and metabolic mechanisms interact in human conditions such as obesity. Both infiltrating immunoinflammatory cells and adipocytes play critical roles in the modulation of metabolic homeostasis, so it is important to understand factors that regulate both adipocyte and immune cell function. A currently favored paradigm for obesity-associated metabolic dysfunction is that chronic macronutrient and/or lipid overload (associated with adiposity) induces cellular stress that initiates and perpetuates an inflammatory cycle and pathophysiological signaling of immunoinflammatory cells and adipocytes. Many lipid mediators exert their biological effects by binding to cognate receptors, such as G-protein-coupled receptors and Toll-like receptors. This process is tightly regulated under normal physiological conditions, and any disruption can initiate disease processes. Observations that cellular lipid loading (associated with adiposity) initiates inflammatory events has encouraged studies on the role of lipid mediators. In this review, we speculate that lipid mediators act on important immune receptors to induce low-grade tissue inflammation, which leads to adipocyte and metabolic dysfunction.

/pdf/inflammatory-lipid-mediators-in-adipocyte-function-and-4zy5s5v81p.pdf

Lindsay Brown

Papers

Rat models of hypertension, cardiac hypertrophy and failure.

High-carbohydrate, high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats

Omega-3 fatty acids and metabolic syndrome: Effects and emerging mechanisms of action

Rodent Models for Metabolic Syndrome Research

Inflammatory lipid mediators in adipocyte function and obesity