Severe Caloric Restriction Research Articles

COCOA (Theobroma cacao) POLYPHENOL-RICH EXTRACT INCREASES THE CHRONOLOGICAL LIFESPAN OF Saccharomyces cerevisiae

BACKGROUND: Saccharomyces cerevisiae is a model organism with conserved aging pathways. Yeast chronological lifespan experiments mimic the processes involved in human non-dividing tissues, such as the nervous system or skeletal muscle, and can speed up the search for biomolecules with potential anti-aging effects before proceeding to animal studies. OBJECTIVE: To test the effectiveness of a cocoa polyphenol-rich extract (CPE) in expanding the S. cerevisiae chronological lifespan in two conditions: in the stationary phase reached after glucose depletion and under severe caloric restriction. MEASUREMENTS: Using a high-throughput method, wild-type S. cerevisiae and its mitochondrial manganese-dependent superoxide dismutase null mutant (sod2Δ) were cultured in synthetic complete dextrose medium. After 2 days, 0, 5 and 20 mg/ml of CPE were added, and viability was measured throughout the stationary phase. The effects of the major components of CPE were also evaluated. To determine yeast lifespan under severe caloric restriction conditions, cultures were washed with water 24 h after the addition of 0 and 20 mg/ml of CPE, and viability was followed over time. RESULTS : CPE increased the chronological lifespan of S. cerevisiae during the stationary phase in a dose-dependent manner. A similar increase was also observed in (sod2Δ). None of the major CPE components (theobromine, caffeine, maltodextrin, (-)-epicatechin, (+)-catechin and procyanidin B2) was able to increase the yeast lifespan. CPE further increased the yeast lifespan under severe caloric restriction. CONCLUSION: CPE increases the chronological lifespan of S. cerevisiae through a SOD2-independent mechanism. The extract also extends yeast lifespan under severe caloric restriction conditions. The high-throughput assay used makes it possible to simply and rapidly test the efficacy of a large number of compounds on yeast aging, requiring only small amounts, and is thus a convenient screening assay to accelerate the search for biomolecules with potential anti-aging effects.

Koschei the immortal and anti-aging drugs.

In Slavic folklore, Koschei the Immortal was bony, thin and lean. Was his condition caused by severe calorie restriction (CR)? CR deactivates the target of rapamycin pathway and slows down aging. But the life-extending effect of severe CR is limited by starvation. What if Koschei's anti-aging formula included rapamycin? And was rapamycin (or another rapalog) combined with commonly available drugs such as metformin, aspirin, propranolol, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors.

Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes

ObjectiveHyperglycemia improves when patients with type 2 diabetes are placed on a weight-loss diet. Improvement typically occurs soon after diet implementation. This rapid response could result from low fuel supply (calories), lower carbohydrate content of the weight-loss diet, and/or weight loss per se. To differentiate these effects, glucose, insulin, C-peptide and glucagon were determined during the last 24h of a 3-day period without food (severe calorie restriction) and a calorie-sufficient, carbohydrate-free diet. Research designSeven subjects with untreated type 2 diabetes were studied. A randomized-crossover design with a 4-week washout period between arms was used. MethodsResults from both the calorie-sufficient, carbohydrate-free diet and the 3-day fast were compared with the initial standard diet consisting of 55% carbohydrate, 15% protein and 30% fat. ResultsThe overnight fasting glucose concentration decreased from 196 (standard diet) to 160 (carbohydrate-free diet) to 127mg/dl (fasting). The 24h glucose and insulin area responses decreased by 35% and 48% on day 3 of the carbohydrate-free diet, and by 49% and 69% after fasting. Overnight basal insulin and glucagon remained unchanged. ConclusionsShort-term fasting dramatically lowered overnight fasting and 24h integrated glucose concentrations. Carbohydrate restriction per se could account for 71% of the reduction. Insulin could not entirely explain the glucose responses. In the absence of carbohydrate, the net insulin response was 28% of the standard diet. Glucagon did not contribute to the metabolic adaptations observed.

20 years of leptin: role of leptin in energy homeostasis in humans.

The hyperphagia, low sympathetic nervous system tone, and decreased circulating concentrations of bioactive thyroid hormones that are common to states of congenital leptin deficiency and hypoleptinemia following and during weight loss suggest that the major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. In weight-reduced humans, these phenotypes together with pronounced hypometabolism and increased parasympathetic nervous system tone create the optimal circumstance for weight regain. Based on the weight loss induced by leptin administration in states of leptin deficiency (obese) and observed similarity of phenotypes in states of congenital and dietary-induced states of hypoleptinemia (reduced obese), it has been suggested that exogenous leptin could potentially be useful in initiating, promoting, and sustaining weight reduction. However, the responses of human beings to exogenous leptin administration are dependent not only on extant energy stores but also on energy balance. Leptin administration to humans at usual weight has little, if any, effect on body weight while leptin administration during weight loss mitigates hunger, especially if given in supraphysiological doses during severe caloric restriction. Leptin repletion is most effective following weight loss by dietary restriction. In this state of weight stability but reduced energy stores, leptin at least partially reverses many of the metabolic, autonomic, neuroendocrine, and behavioral adaptations that favor weight regain. The major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. Leptin, and pharmacotherapies affecting leptin signaling pathways, is likely to be most useful in sustaining weight loss.

Proteome adaptation of Saccharomyces cerevisiae to severe calorie restriction in Retentostat cultures.

Stationary-phase, carbon-starved shake-flask cultures of Saccharomyces cerevisiae are popular models for studying eukaryotic chronological aging. However, their nutrient-starved physiological status differs substantially from that of postmitotic metazoan cells. Retentostat cultures offer an attractive alternative model system in which yeast cells, maintained under continuous calorie restriction, hardly divide but retain high metabolic activity and viability for prolonged periods of time. Using TMT labeling and UHPLC-MS/MS, the present study explores the proteome of yeast cultures during transition from exponential growth to near-zero growth in severely calorie-restricted retentostats. This transition elicited protein level changes in 20% of the yeast proteome. Increased abundance of heat shock-related proteins correlated with increased transcript levels of the corresponding genes and was consistent with a strongly increased heat shock tolerance of retentostat-grown cells. A sizable fraction (43%) of the proteins with increased abundance under calorie restriction was involved in oxidative phosphorylation and in various mitochondrial functions that, under the anaerobic, nongrowing conditions used, have a very limited role. Although it may seem surprising that yeast cells confronted with severe calorie restriction invest in the synthesis of proteins that, under those conditions, do not contribute to fitness, these responses may confer metabolic flexibility and thereby a selective advantage in fluctuating natural habitats.

Behavioral and neural correlates of acute and scheduled hunger in C57BL/6 mice.

In rodents, daily feeding schedules induce food anticipatory activity (FAA) rhythms with formal properties suggesting mediation by food-entrained circadian oscillators (FEOs). The search for the neuronal substrate of FEOs responsible for FAA is an active area of research, but studies spanning several decades have yet to identify unequivocally a brain region required for FAA. Variability of results across studies leads to questions about underlying biology versus methodology. Here we describe in C57BL/6 male mice the effects of varying the ‘dose’ of caloric restriction (0%, 60%, 80%, 110%) on the expression of FAA as measured by a video-based analysis system, and on the induction of c-Fos in brain regions that have been implicated in FAA. We determined that more severe caloric restriction (60%) leads to a faster onset of FAA with increased magnitude. Using the 60% caloric restriction, we found little evidence for unique signatures of neuronal activation in the brains of mice anticipating a daily mealtime compared to mice that were fasted acutely or fed ad-libitum–even in regions such as the dorsomedial and ventrolateral hypothalamus, nucleus accumbens, and cerebellum that have previously been implicated in FAA. These results underscore the importance of feeding schedule parameters in determining quantitative features of FAA in mice, and demonstrate dissociations between behavioral FAA and neural activity in brain areas thought to harbor FEOs or participate in their entrainment or output.

St. Ambrose, Euthanasia, and Antisenescence Arguments: Death as a Good?

I. Introduction ANTISENESCENCE TECHNOLOGIES AIM to extend human life, some say by hundreds of years, others indefinitely. Theoretically, indefinite extension is a possibility through, for example, cell replacement therapy. Even now, research suggests that severe caloric restriction can exert significant effects on life extension. (1) Whereas human enhancement in terms of extending healthy life sounds attractive, there are notable ethical concerns that cannot be ignored. The more sophisticated arguments, ones that do not rest on a utilitarian calculation of good versus bad effects, are certainly noteworthy. For purposes of this article, I will not defend such arguments, but will rest content to canvas basic lines of thought they embrace. Representative of this small community of detractors who question antisenescence technologies is President's Council on Bioethics under chairmanship of Leon Kass. (2) That council offers following reflections on antisenescence research: the boundaries and shape of life cycle give form and possible meaning to a mortal life. Its virtue consists not so much in that it leads us to death, but in that it reminds us, by its very nature, that we will someday die, and that we must live in a way that takes heed of that reality. (3) Throughout this section of discourse, council focuses reader's attention on value of finitude. Absent a sense of finitude, council argues, one loses a sense of commitment and engagement in life-long projects. Aspiration to accomplish something and to be creative is lost as is a desire for renewal, latter of which amounts to a lost desire for children. They note, an era of age retardation we might in practice therefore live under an even more powerful preoccupation with death, but one that leads us not to commitment, engagement, urgency, and renewal, but rather to anxiety, self-absorption, and preoccupation with any bodily mishap or every new antisenescence measure. (4) The basic point council is making is that life cycle, and what that cycle entails in regard to finitude and death, is something of value. That our lives will come to an end is a value; it forces us, however unwillingly, to focus our attention and activities on this finite length of time. In this sense, where death is understood to entail finitude and a sense of finitude is a good thing, death is seen as a good. Viewing death as a good thing is neither a novel nor even a radical idea in Christian intellectual tradition. St. Ambrose's understanding of death outlined in his aptly titled De Bono Mortis (On Good of Death) considers three different senses of death, and at least one is a good, another neutral but possibly good. To quote at length, There are three kinds of death. The first is death of sin, of which it is written: soul which sins shall die. The second is mystical death, when one dies to sin and lives to God.... The third is death by which we complete course and duty of this life, which is to say, separation of soul and body. We note, therefore, that first death ... is evil; second death ... is good; and third has a middle position, for it seems good to righteous men but it is feared by most, and although it frees all, it delights few. But this is not fault of death, but of our own weakness. (5) Note that on traditional understanding of death as separation of soul from body, death is not itself understood as a bad thing; rather, it is condition of our soul that makes it either good or bad. On this point, St. Ambrose expands, saying, Now consider this point: if life is a burden, then death is freedom from it; if life is a punishment, then death is a deliverance; or if there is a judgment after death, there is also a life after death. Is this life, then, not good, or if our life here below is [morally] good, how is death there not good, when no fear of terrible judgment exists there? …

The importance of weight management in type 2 diabetes mellitus

BackgroundThe obesity epidemic is driving the increased prevalence of type 2 diabetes mellitus (T2DM), and the vast majority of patients with T2DM are overweight or obese. Excess body weight is associated with the risk of cardiometabolic complications, which are major causes of morbidity and mortality in T2DM.AimsTo review evidence about effects of weight loss in pre-diabetes and established T2DM.ResultsIn prediabetes, weight loss has been shown to delay the onset or decrease the risk of T2DM, while in established T2DM weight loss has been shown to improve glycaemic control, with severe calorie restriction even reversing the progression of T2DM. Observational studies support the reduction in cardiovascular risk factors following weight loss in patients with T2DM. However, data from the randomised Look AHEAD trial revealed intensive weight loss interventions did not reduce the rate of cardiovascular events in overweight or obese adults with T2DM, and secondary analyses of other large cardiovascular outcomes trials have also been inconclusive. However, besides cardiovascular risk, other documented benefits of weight loss in T2DM include improvements in quality of life, mobility, and physical and sexual function.ConclusionsPhysicians should encourage weight loss in all overweight patients with or at risk of T2DM, and should consider the impact on weight when choosing the most appropriate glucose-lowering therapies for these patients.

Neuroendocrinology of obesity

Recent advances in physiological understanding of obesity have provided a new perspective on its origins and potential treatments. This review is based on published literature in the fields of gut hormone physiology and the neuroendocrinology of obesity. The gut releases several hormones in response to changes in nutritional status. Changes in plasma concentration of these hormones are responded to by central nervous system circuits controlling appetite and energy expenditure. Modified gut hormone secretion is responsible, at least in part, for weight loss after certain forms of bariatric surgery. The extent to which modified gut hormone secretion is also responsible for remission of diabetes after bariatric surgery is contested, as severe calorie restriction alone can restore insulin secretion. Many gut hormone-based drugs are being developed for obesity. If suitable drugs receive marketing authorization, it will be important to discover whether their combined use, mimicking the hormonal milieu after bariatric surgery, can safely cause weight loss and metabolic benefits of similar magnitude to those resulting from bariatric surgery.

The effects of caloric restriction and a high-fat diet on ovarian lifespan and the expression of SIRT1 and SIRT6 proteins in rats.

Caloric restriction (CR) extends mammals' lifespans and suppresses ovary development. Sirtuins are involved in these mechanisms. If, and to what extent CR affects ovarian lifespan and follicle development is largely unknown. We investigated the effects of moderate and severe caloric restriction compared with a high-fat dietary regimen on ovarian follicle reserves in rats. Female Sprague-Dawley rats (n=48) randomly divided into four groups including normal control (NC), 25% caloric restriction (MCR), 45% CR (SCR) and high-fat diet (HF) were maintained on these regimens for 2 months. Histological analysis showed that both the 25 and 45% CR rats had a significantly higher percentage of primordial follicles and a larger number of healthy follicles than the NC rats, whereas the HF rats did not differ significantly from the NC rats. Immunohistochemical analysis revealed that SIRT1 and SIRT6 proteins were present in the nucleus and cytoplasm of the oocytes. The 25% CR diet increased the expression of both SIRT1 and SIRT6 in the ovary, whereas the 45% CR and HF diets caused a decrease in SIRT1 expression. The level of SIRT6 protein did not change with the 45% CR diet, and it appeared slightly lower in the HF than in the NC groups. Caloric restriction may inhibit the transition from primordial to developing follicles and extend the entire growth phase of a follicle to preserve the reserve of germ cells. SIRT1 and SIRT6 are both associated with these effects.

Nutritional Intervention Restores Muscle but Not Kidney Phenotypes in Adult Calcineurin Aα Null Mice

Mice lacking the α isoform of the catalytic subunit of calcineurin (CnAα) were first reported in 1996 and have been an important model to understand the role of calcineurin in the brain, immune system, bones, muscle, and kidney. Research using the mice has been limited, however, by failure to thrive and early lethality of most null pups. Work in our laboratory led to the rescue of CnAα−/− mice by supplemental feeding to compensate for a defect in salivary enzyme secretion. The data revealed that, without intervention, knockout mice suffer from severe caloric restriction. Since nutritional deprivation is known to significantly alter development, it is imperative that previous conclusions based on CnAα−/− mice are revisited to determine which aspects of the phenotype were attributable to caloric restriction versus a direct role for CnAα. In this study, we find that defects in renal development and function persist in adult CnAα−/− mice including a significant decrease in glomerular filtration rate and an increase in blood urea nitrogen levels. These data indicate that impaired renal development we previously reported was not due to caloric restriction but rather a specific role for CnAα in renal development and function. In contrast, we find that rather than being hypoglycemic, rescued mice are mildly hyperglycemic and insulin resistant. Examination of muscle fiber types shows that previously reported reductions in type I muscle fibers are no longer evident in rescued null mice. Rather, loss of CnAα likely alters insulin response due to a reduction in insulin receptor substrate-2 (IRS2) expression and signaling in muscle. This study illustrates the importance of re-examining the phenotypes of CnAα−/− mice and the advances that are now possible with the use of adult, rescued knockout animals.

Effects of severe caloric restriction from birth on the hearts of adult rats

There has been increasing evidence suggesting that a severe caloric restriction (SCR) (above 40%) has beneficial effects on the hearts of rats. However, most of the reports have focused on the effects of SCR that started in adulthood. We investigated the consequences of SCR on the hearts of rats subjected to SCR since birth (CR50). From birth to the age of 3 months, CR50 rats were fed 50% of the food that the ad libitum group (AL) was fed. Thereafter, a maximal aerobic test was performed to indirectly evaluate global cardiovascular function. Indices of contractility (+dT/dt) and relaxation (-dT/dt) were analyzed in isolated heart preparation, and cardiomyocyte diameter, number, density, and myocardium collagen content were obtained through histologic analysis. Ventricular myocytes were isolated, using standard methods to evaluate phosphorylated AKT levels, and Ca(2+) handling was evaluated with a combination of Western blot analysis, intracellular Ca(2+) imaging, and confocal microscopy. CR50 rats exhibited increased aerobic performance and cardiac function, as shown by the increase in ±dT/dt. Despite the smaller cardiomyocyte diameter, CR50 rats had an increased heart-body weight ratio, increased cardiomyocyte density and number, and similar levels of myocardium collagen content, compared with AL rats. AKT was hyperphosphorylated in cardiomyocytes from CR50 rats, and there were no significant differences in Ca(2+) transient and SERCA2 levels in cardiomyocytes between CR50 and AL rats. Collectively, these observations reveal the beneficial effects of a 50% caloric restriction on the hearts of adult rats restricted since birth, which might involve cardiomyocyte AKT signaling.

Emotional Abuse in Sport: A Case Study of Trichotillomania in a Prepubescent Female Gymnast

Despite improved legislation in most countries, child abuse in sport continues to exist but is a problem which is often under reported or ignored. In elite sport ‘suffering’ is not uncommon and hence sometimes child abuse is sometimes unrecognised, de-emphasised or easily dismissed as part of a collective experience that is perceived to be necessary to ‘create’ elite athletes. However, even swearing, anger, raised voices and negative comments directed at child athletes by coaches is considered abuse and can, when regular and routine, cause long term wellbeing and health issues. Self-harm can be a consequence and here self-harm in the form of trichotillomania, self hair-pulling, is reported for the first time as a secondary consequence of abuse. The 12 year old female gymnast, subject of this case study, presented with this impulse control disorder as defined by the American Psychiatric Association and was successfully treated using cognitive behavioural therapy. However, the training environment, including coach behaviour, did not change and so the gymnast remained at risk of recurrence of self-harm. Such environments in sport have many characteristics in common with and reminiscent of religious cults; sacrifice, isolation, shared obsession, a charismatic leader, and often in the presence of severe calorie restriction. As a consequence of ageing, growth, injury and an unchanging abusive environment, a year later the gymnast retired from the sport.

Association Between Diet During Preadolescence and Adolescence and Risk for Breast Cancer During Adulthood

It is increasingly evident that diet during preadolescence and adolescence has important consequences for breast cancer during adulthood. However, only a few epidemiologic studies have been conducted on the relationship between diet during preadolescence and adolescence, and cancer during adulthood. This situation is partly because of methodological challenges such as the long latency period, the complexity of breast cancer, the lack of validated diet assessment tools, and the large number of subjects that must be followed, all of which increase costs. In addition, funding opportunities are few for such studies. Results from the small number of epidemiologic studies are inconsistent, but evidence is emerging that specific aspects of the diet during preadolescence and adolescence are important. For example, during preadolescence and adolescence, severe calorie restriction with poor food quality, high total fat intake, and alcohol intake tend to increase risk, whereas high soy intake decreases risk. Research on preadolescent and adolescent diet is a paradigm shift in breast cancer investigations. This research paradigm has the potential to produce transformative knowledge to inform breast cancer prevention strategies through dietary intervention during preadolescence and adolescence, rather than later in life, as is current practice, when it is perhaps less effective. Methodological challenges that have plagued the field might now be overcome by leveraging several existing large-scale cohort studies in the U.S. and around the world to investigate the role of diet during preadolescence and adolescence in risk for adult breast cancer.

Severe caloric restriction in young women during World War II and subsequent breast cancer risk

The objective of the study was to examine the impact of WWII-related caloric restriction (CR) on subsequent breast cancer (BC) risk based on individual exposure experiences and whether this effect was modified by age at exposure. We compared 65 breast cancer patients diagnosed between 2005-2010 to 200 controls without breast cancer who were all members of various organizations for Jewish WWII survivors in Israel. All participants were Jewish women born in Europe prior to 1945 who lived at least 6 months under Nazi rule during WWII and immigrated to Israel after the war. We estimated CR using a combined index for hunger and used logistic regression models to estimate the association between CR and BC, adjusting for potential confounders. Women who were severely exposed to hunger had an increased risk of BC (OR=5.0, 95% CI= 2.3-10.8) compared to women who were mildly exposed. The association between CR and BC risk was stronger for women who were exposed at a younger age (0-7 years) compared to the risk of BC in women exposed at ≥ 14 years (OR= 2.8, 95% CI=1.3-6.3). Severe exposure to CR is associated with a higher risk for BC decades later, and may be generalized to other cases of severe starvation during childhood that may have long-term effects on cancer in adulthood.

The ghrelin-growth hormone axis preserves gluconeogenesis to maintain blood glucose levels during starvation

Background The octanoylated peptide ghrelin stimulates growth hormone (GH) secretion during severe calorie restriction in mice, which preserves fasting blood sugar after body fat has been depleted. Genetic deletion of ghrelin-O-acyltransferase (GOAT, which octanoylates ghrelin) renders mice ghrelin-deficient and abrogates the normal rise in GH after several days of calorie restriction, resulting in profound hypoglycemia. Administration of either ghrelin or GH to GOAT knockout mice restores the ability to maintain fasting blood sugar levels during prolonged calorie restriction. The mechanism of hypoglycemia in ghrelin-deficient mice has not been described previously.

An Alternative Dietary Strategy to Make Weight While Improving Mood, Decreasing Body Fat, and Not Dehydrating: A Case Study of a Professional Jockey

Professional jockeys are unique among weight-making athletes, as they are often required to make weight daily and, in many cases, all year-round. Common methods employed by jockeys include dehydration, severe calorie restriction, and sporadic eating, all of which have adverse health effects. In contrast, this article outlines a structured diet and exercise plan, employed by a 22-yr-old professional National Hunt jockey in an attempt to reduce weight from 70.3 to 62.6 kg, that does not rely on any of the aforementioned techniques. Before the intervention, the client's typical daily energy intake was 8.2 MJ (42% carbohydrate [CHO], 36% fat, 22% protein) consumed in 2 meals only. During the 9-wk intervention, daily energy intake was approximately equivalent to resting metabolic rate, which the athlete consumed as 6 meals per day (7.6 MJ, 46% CHO, 19% fat, 36% protein). This change in frequency and composition of energy intake combined with structured exercise resulted in a total body-mass loss of 8 kg, corresponding to reductions in body fat from 14.5% to 9%. No form of intentional dehydration occurred throughout this period, and mean urine osmolality was 285 mOsm/kg (SD 115 mOsm/kg). In addition, positive changes in mood scores (BRUMS scale) also occurred. The client was now able to ride light for the first time in his career without dehydrating, thereby challenging the cultural practices inherent in the sport.

Surviving starvation: essential role of the ghrelin-growth hormone axis

Chronic starvation is a repeated threat to survival of animals of all species. Indeed, about 15% of the current human population is estimated to suffer from severe malnutrition, and one-half of all deaths in children less than 5 years of age (~6 million deaths per year) arise from malnutrition. Over the centuries, starvation has exerted profound evolutionary pressure that has selected for a variety of adaptive mechanisms to support life. Paramount among these mechanisms is the necessity to maintain blood sugar concentrations sufficient for brain function. The adaptive mechanisms are particularly strained when chronic starvation has depleted the body of its other source of energy – namely, fatty acids stored as triglycerides. Recently, our laboratory has begun to study the adaptation to chronic starvation, focusing on the essential roles of two peptide hormones, ghrelin and growth hormone. Ghrelin, a peptide hormone secreted by neuroendocrine cells in the stomach, was identified in 1999 by Kojima and Kangawa by its ability to stimulate release of growth hormone. In rodents and humans, plasma ghrelin rises before meals and declines after eating. Administration of excess ghrelin increases food intake, but knockout mice lacking ghrelin or its receptor have normal weight. Therefore, the true function of ghrelin has been enigmatic. Ghrelin is unique in that it requires a covalently attached 8-carbon fatty acid for activity, a modification conserved in all vertebrates. We identified ghrelin O-acyltransferase (GOAT), the enzyme that attaches octanoate to ghrelin. GOAT knockout mice cannot produce active ghrelin. Like ghrelin knockouts, GOAT knockouts have normal body weight. When these knockout mice are placed on a 60% calorie-restricted diet for 8 days, they are unable to maintain normal blood glucose and die. Restoration of ghrelin or growth hormone prevents death. Thus, ghrelin maintains blood glucose under conditions of severe calorie restriction, a function essential for survival in chronically starved rodents. Recent data on the mechanism by which the ghrelin-growth hormone axis preserves blood glucose will be presented.

Targeted Deletion of Jun/AP-1 in Alveolar Epithelial Cells Causes Progressive Emphysema and Worsens Cigarette Smoke–Induced Lung Inflammation

Chronic obstructive pulmonary disease appears to occur slowly and progressively over many years, with both genetic factors and environmental modifiers contributing to its pathogenesis. Although the c-Jun/activator protein 1 transcriptional factor regulates cell proliferation, apoptosis, and inflammatory responses, its role in lung pathogenesis is largely unknown. In this study, we report decreased expression levels of c-Jun mRNA and protein in the lung tissues of patients with advanced chronic obstructive pulmonary disease, and the genetic deletion of c-Jun specifically in alveolar epithelial cells causes progressive emphysema with lung inflammation and alveolar air space enlargement, which are cardinal features of emphysema. Although mice lacking c-Jun specifically in lung alveolar epithelial cells appear normal at the age of 6 weeks, when exposed to long-term cigarette smoke, c-Jun-mutant mice display more lung inflammation with perivascular and peribronchiolar infiltrates compared with controls. These results demonstrate that the c-Jun/activator protein 1 pathway is critical for maintaining lung alveolar cell homeostasis and that loss of its expression can contribute to lung inflammation and progressive emphysema.

Immediate and long-term effects of addition of exercise to a 16-week very low calorie diet on low-grade inflammation in obese, insulin-dependent type 2 diabetic patients

ObjectiveTo assess the short- and long-term effects of addition of exercise to a very low calorie diet (VLCD) on low-grade inflammation in obese patients with type 2 diabetes mellitus (T2DM). MethodsTwenty seven obese, insulin-dependent T2DM patients followed a 4-month VLCD with (n=13) or without (n=14) exercise and were followed up to 18months. Anthropometric measurements, metabolic and inflammatory parameters were assessed before, directly after the intervention and at 6 and 18months follow-up. The same measurements were performed only once in 56 healthy lean and 56 healthy obese controls. ResultsAt baseline hsCRP, IL10 and IL8 were significantly elevated in obese T2DM compared to lean healthy controls. After 4months, despite substantial weight loss (−25.4±1.3kg), neither the VLCD nor VLCD+exercise had an effect on plasma cytokines. At 6months, in the weight-stabilizing period, measures of low-grade inflammation had decreased substantially and equally in both intervention groups. Despite subsequent weight regain, beneficial effect was sustained up to 18months in both groups, except for IL1 and hsCRP which had returned to baseline in the VLCD-only group. ConclusionOur findings suggest that severe caloric restriction increases cytokine production by adipose tissue macrophages and that the beneficial effects of weight loss become apparent only in the eucaloric state.