By Max Bingham, PhD
A Mechanism for the Thermoregulation of Obesity and Its Centers on the Brain: Animal Data
A key approach to the treatment of obesity revolves around increased energy expenditure to reduce body weight. One approach to achieve this is to increase energy expenditure via the so-called browning of adipose tissue. Methods to achieve this are varied but well described. The mechanisms behind it though are far from clear. In an answer to this, Contreras et al. (p. 87) suggest that a specific protein, glucose-regulated protein 78 kDa (GRP78), might be central to a mechanism that regulates the browning of adipose tissue and thus the upregulation of energy expenditure. The key, they say, is the function of the protein in the hypothalamus—a key area of the brain involved in the regulation of energy expenditure. The study involved the use of various rat models and a combination of many measures targeting metabolic, histological, physiological, genetic, pharmacological, and metabolic outcomes. They report that rats fed a high-fat diet did experience significant hypothalamic endoplasmic reticulum stress but that genetic manipulation of GRP78 in a specific part of the hypothalamus (the ventromedial nucleus) resulted in reverted obese and metabolic phenotypes. Significantly, they say that this was independent of feeding rates and leptin levels and that it resulted in thermogenic activation of brown adipose tissue and the browning of white adipose tissue. They go on to describe experiments that seem to conclusively prove the case. Commenting on the experiments more widely, author Miguel López told Diabetes: “It has been proposed that browning of white fat has therapeutic potential to promote body fat reduction. Although several mechanisms have been suggested, the neuronal pathways within the central nervous system that control white adipose tissue browning have remained unclear. Our data provide evidence that amelioration of endoplasmic reticulum stress in the ventromedial nucleus by GRP78 is a central mechanism regulating white adipose tissue browning. This evidence may indicate that targeting the hypothalamic control of white adipose tissue browning may be a potential strategy against obesity and associated morbidities.”
Representative infrared thermal images of the effect of GRP78 overexpression in the ventromedial nucleus of the hypothalamus of rats fed a high-fat diet (HFD) on brown adipose tissue thermogenesis. Ad, adenovirus.
Renal and Cardiovascular Protection Through Calorie Restriction in Type 2 Diabetes
Calorie restriction in patients with type 2 diabetes and abdominal obesity might result in significant reductions in glomerular filtration rate, a measure used to estimate renal function and chronic kidney disease risk, according to the results of a small randomized controlled trial reported by Ruggenenti et al. (p. 75). The authors also suggest calorie restriction likely results in improved glucose disposal, insulin sensitivity, and a long list of other cardiovascular risk factors. Calorie restriction has previously been linked to cardiovascular but not renal function improvements in a human population with diabetes in a clinical trial. The outcomes are from a fairly small study that compared the effect of calorie restriction(n = 34) and a standard diet (n = 36) on glomerular filtration rate in the patients over a period of 6 months. The authors report the intensive approaches used to drive down or maintain caloric intake, depending on the group, and a range of measurements used at baseline and follow-up. In short, they report that calorie restriction resulted in significant reductions in glomerular filtration rate and was also associated with reductions or general improvements in BMI, waist circumference, blood pressure, heart rate, HbA1c, blood glucose, cholesterol levels, and C-reactive protein, among others. Commenting more widely on the study, author Giuseppe Remuzzi said: “This was the first study that formally evaluated the effects of calorie restriction on kidney function in obese patients with diabetes with hyperfiltration. Despite the relative small number of patients, the use of gold-standard techniques for the measurement of glomerular filtration rate, albuminuria, and insulin sensitivity increased the statistical power of the analyses and the robustness of the findings. Moreover, despite the highly labor-intensive design, the study had a high retention rate of enrolled participants and good adherence to study interventions. Thus, compliance to dietary recommendations is an achievable goal, provided dietitians and doctors are strongly motivated and are devoted enough to also transmit their motivations to more disinclined patients.”
Inositol-Requiring Enzyme 1 and Diabetic Wound Healing Mediated by MicroRNAs
A study by Wang et al. (p. 177) suggests that the key to improved diabetic wound healing may lie with a specific enzyme involved in angiogenesis following wounding and the fact that diabetes likely results in its suppression. As well as uncovering a potential new mechanism for rescuing angiogenesis, they also demonstrate an approach to actually improve diabetic wound healing. The study mainly investigated bone marrow progenitor cells in vitro that had been isolated from adult mice with type 2 diabetes and controls. Then using mainly recombinant virus–mediated transfection approaches, they were able to investigate the role of the enzyme, inositol-requiring enzyme 1 (IRE1α), on angiogenesis and finally wound healing in the mice. Initial experiments revealed that the cells taken from diabetic mice had repressed levels of IRE1α protein expression. They also had impaired angiogenic function that could be rescued through adenovirus-mediated IRE1α expression. Subsequent investigations then uncovered an intricate pathway where it appears that IRE1α disrupts the biogenesis of a range of microRNAs and particularly their precursors, which in turn suppresses an angiogenic factor called angiopoietin 1 (ANGPT1) in diabetic wounds. In short, the suppression of IRE1α by diabetes knocks out the stress response pathway, with the result being impaired angiogenesis and wound healing. To prove the point, the authors then applied combinations of cells variously upregulated with IRE1α (or not) directly to wounds inflicted on the different groups of mice and showed that equal wound healing can be achieved in healthy controls and mice with diabetes when IRE1α is restored. Commenting more widely on their work, authors Jie-Mei Wang and Kezhong Zhang said: “The study provides a novel concept that an IRE1α-mediated unconventional stress response pathway plays an important role in promoting angiogenesis and diabetic wound healing. These findings will have important implications in drug discovery and therapeutics development for tissue repair and regeneration in diabetes.”
Schema of hypothesis. Under the diabetic condition, IRE1α RNase activity degrades microRNA (miR) precursors, including pre-miR-466 and pre-miR-200. These two miR families repress ANGPT1 mRNA translation, leading to downregulation of ANGPT1. Activity of IRE1α is suppressed in diabetic bone marrow–derived progenitor cells. As a result, the downregulated ANGPT1 by increased miR-466 and miR-200 activities contributes to decreased angiogenesis and ineffective wound tissue repair under the diabetic conditions. ER, endoplasmic reticulum.
Mitochondrial Oxidative Capacity Impaired in Insulin Resistance and Prediabetes
Insulin resistance and prediabetes appear to be linked to impaired mitochondrial capacity even in individuals without diabetes. This is according to Fabbri et al. (p. 170) who now suggest that mitochondrial oxidative capacity should be considered as a possible therapeutic target for diabetes and a potential diagnostic for prediabetes. The outcomes are a result of a cross-sectional study that investigated mitochondrial capacity in 248 individuals without diabetes using 31P-magnetic resonance spectroscopy. This is a technique that can noninvasively measure phosphocreatine in muscle cells. Phosphocreatine is rapidly generated by mitochondria following exercise and acts as a reserve of high-energy phosphates in skeletal muscle. It can therefore be used to assess mitochondrial oxidative capacity in vivo. The participants were also assessed for prediabetes status, insulin resistance, estimated hyperglycemia exposure, and a range of potential confounding factors. Logistic and linear regression modeling was then used to investigate the existence of associations with mitochondrial oxidative capacity. According to the authors, after adjusting for confounders, impaired mitochondrial oxidative capacity was associated with a higher likelihood of having prediabetes, more severe insulin resistance, and lower insulin sensitivity. Severity and duration of hyperglycemia was also independently associated with impaired mitochondrial function. Although accounting for some limitations of the study, they recommend that mitochondrial capacity now be considered as an integral part of insulin resistance and thus a therapeutic target for diabetes. Commenting more widely on this aspect of the study, author Luigi Ferrucci said: “While several drugs that may improve mitochondrial function are already in the pipeline of development of many drug companies, a straightforward and rapid approach to increase mitochondrial function is to exercise. Also, new high-throughput methods to estimate mitochondrial DNA copy numbers are being developed. Studies are also being conducted to establish whether mitochondrial DNA copy number in circulating cells is a valid biomarker of global mitochondria function. This research may provide physicians with a tool for early diagnosis of prediabetes status.”
