Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

/pdf/cell-biology-of-ischemia-reperfusion-injury-1rdtb8k8os.pdf

Cell Biology of Ischemia/Reperfusion Injury

Background: There has been increasing interest in the concept that exposures to environmental chemicals may be contributing factors to the epidemics of diabetes and obesity. On 11–13 January 2011, ...

Role of Environmental Chemicals in Diabetes and Obesity: A National Toxicology Program Workshop Review

Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These “weight-reduced” phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre–weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre–weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state.

/pdf/low-dose-leptin-reverses-skeletal-muscle-autonomic-and-4ibmln54s8.pdf

Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight

http://blumberg-serv.bio.uci.edu/reprints/grun_MCE-2009.pdf

Endocrine disrupters as obesogens.

Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.

/pdf/mechanisms-linking-inflammation-to-insulin-resistance-5ez34wwq1i.pdf

Mechanisms Linking Inflammation to Insulin Resistance

Previously we have reported that maternal malnutrition during lactation programmes body weight and thyroid function in the adult offspring. In the present study we evaluated the effect of maternal protein restriction during lactation upon body composition and hormones related to glucose homeostasis in adult rats. During lactation, Wistar lactating rats and their pups were divided into two experimental groups: control (fed a normal diet; 23 % protein) and protein-restricted (PR; fed a diet containing 8 % protein). At weaning, offspring received a normal diet until they were 180 d old. Body weight (BW) and food intake were monitored. Serum, adrenal glands, visceral fat mass (VFM) and carcasses were collected. PR rats showed lower BW ( − 13 %; P < 0·05), VFM ( − 33 %; P < 0·05), total body fat ( − 33 %; P < 0·05), serum glucose ( − 7 %; P < 0·05), serum insulin ( − 26 %, P < 0·05), homeostasis model assessment index ( − 20 %), but higher total adrenal catecholamine content (+90 %; P < 0·05) and serum corticosterone concentration (+51 %; P < 0·05). No change was observed in food intake, protein mass or total body water. The lower BW of PR rats is due to a reduction of white fat tissue, probably caused by an increase in lipolysis or impairment of lipogenesis; both effects could be related to higher catecholaminergic status, as well as to hypoinsulinaemia. To conclude, changes in key hormones which control intermediary metabolism are programmed by maternal protein restriction during lactation, resulting in BW alterations in adult rats.

/pdf/maternal-low-protein-diet-during-lactation-programmes-body-3s8gl5k6il.pdf

Maternal low-protein diet during lactation programmes body composition and glucose homeostasis in the adult rat offspring

Programming is an epigenetic phenomenon by which nutrition, environment and stress acting in a critical period earlier in life change the organism‘s development. This process was evolutionarily select

Neonatal Programming of Neuroimmunomodulation – Role of Adipocytokines and Neuropeptides

Epidemiological studies show a higher prevalence of obesity in children from smoking mothers and smoking may affect human thyroid function. To evaluate the mechanism of smoking as an imprinting factor for these dysfunctions, we evaluated the programming effects of maternal nicotine (NIC) exposure during lactation. Two days after birth, osmotic minipumps were implanted in lactating rats, divided into: NIC (6 mg/kg per day s.c.) for 14 days; Control - saline. All the significant data were P<0.05 or less. Body weight was increased from 165 days old onwards in NIC offspring. Both during exposure (at 15 days old) and in adulthood (180 days old), NIC group showed higher total fat (27 and 33%). In addition, NIC offspring presented increased visceral fat and total body protein. Lipid profile was not changed in adulthood. Leptinemia was higher at 15 and 180 days old (36 and 113%), with no changes in food intake. Concerning the thyroid status, the 15-days-old NIC offspring showed lower serum-free tri-iodothyronine (FT(3)) and thyroxine (FT(4)) with higher TSH. The 180-days-old NIC offspring exhibited lower TSH, FT(3), and FT(4)). In both periods, liver type 1 deiodinase was lower (26 and 55%). We evidenced that NIC imprints a neonatal thyroid dysfunction and programs for a higher adiposity, hyperleptinemia, and secondary hypothyroidism in adulthood. Our study identifies lactation as a critical period to NIC programming for obesity, with hypothyroidism being a possible contributing factor.

/pdf/short-and-long-term-effects-of-maternal-nicotine-exposure-53g5aqxno3.pdf

Short- and long-term effects of maternal nicotine exposure during lactation on body adiposity, lipid profile, and thyroid function of rat offspring

For this study, we have determined the effects of neonatal leptin treatment on the evolution of body weight. Experiment 1: pups were divided into two groups: LepF - injected with leptin (8 micro g/100 g of body weight) for the first 10 days of lactation and control (C) - receiving saline. Experiment 2: pups were divided into two groups: LepL - injected with the same leptin concentration of experiment one for the last 10 days of lactation, and C, which received saline. Body weight and food intake were monitored until age 150 days, after which leptin concentrations were measured by ELISA. The LepF group had a significant increase in body weight (p < 0.05) from day 98 onward, in food intake (p < 0.05) from day 74 onward, and higher serum leptin concentration compared to the control (108 %, p < 0.05). The LepL group had a significant increase in body weight (p < 0.05) from day 113 onward, in food intake from day 121 onward (p < 0.001), and higher serum leptin concentration compared to controls (6.9 %, p < 0.05). These results suggest that both periods of lactation constituted a critical window for body weight and food intake programming, but the effects are more marked when the leptin is injected within the first ten days.

Leptin treatment during the neonatal period is associated with higher food intake and adult body weight in rats.

Some studies have shown that the mother's nutritional condition may influence offspring's endocrine function through metabolic imprinting. Recently, we showed that the kind of maternal malnutrition during lactation affects adult body weight of the offspring and it is related to milk composition. We studied lactating rats fed an 8% protein-restricted diet (PR), a control 23% protein diet (C), and an energy-restricted diet group (ER). After weaning, all animals received a normal diet until they were 180 days of age. At this time, the animals received a single i. p. injection of 1 3 1 I and were sacrificed 2 h after the injection. Total triiodothyronine (TT 3 ) and total thyroxin (TT 4 ) serum concentrations were measured by enzyme immunoassay. The PR group had significantly a higher thyroid 1 3 1 I uptake, TT 3 serum concentration and in TT 4 serum concentration, compared to the controls. The ER group had only significantly higher TT 3 serum concentration. These results showed that thyroid function regulation in adulthood may depend on maternal nutritional condition during lactation. Probably, PR group had a high thyroid function, whereas the ER group only had an increase in the deiodination of T 4 The hyperthyroidism in the PR group could explain the low body weight observed in those animals.

M. C. F. Passos

Papers

Maternal low-protein diet during lactation programmes body composition and glucose homeostasis in the adult rat offspring

Neonatal Programming of Neuroimmunomodulation – Role of Adipocytokines and Neuropeptides

Short- and long-term effects of maternal nicotine exposure during lactation on body adiposity, lipid profile, and thyroid function of rat offspring

Leptin treatment during the neonatal period is associated with higher food intake and adult body weight in rats.

Long-term effects of malnutrition during lactation on the thyroid function of offspring.