Obesity and life style-related diseases have become major burdens to global health. Not having effective diet therapy that patients can adhere to makes life-style modification difficult. Many diet ...therapies are developed based on solid scientific evidence in terms of nutrition. However, how to execute such nutritionally-effective diet therapy is not established, nor based on solid science. Current practices are mostly developed by trial-and-error (experience-based), and they do not have solid bases on how eating behavior is regulated. Therefore, one of the major bottlenecks for implementing nutritionally-effective diet therapy is our lack of understanding of the molecular and neural bases of eating behavior. Based on the concept of nutrition, we eat to maintain homeostasis, and therefore, we should be satisfied once the needs are met by the supplies. However, that is only a part of the picture regarding eating. Palatable foods, which stimulate the hedonic system, and the experience-based prediction system work in concert to regulate eating. The information that conveys needs and supplies is multi-modal, each mode working at different timing to modulate each system. Therefore, eating behavior is complex, and the whole picture remains elusive. In particular, how we sense, calculate, and predict the needs and supplies of calories and each macronutrient remains to be understood. In this minireview, the frontiers in our understanding of the mechanism that regulates eating are briefly overviewed, as a summary of the IUNS-ICN symposium entitled “Molecular and neural bases of nutrition-based feeding decision-making.”
We are what we eat. There are three aspects of feeding: what, when, and how much. These aspects represent the quantity (how much) and quality (what and when) of feeding. The quantitative aspect of ...feeding has been studied extensively, because weight is primarily determined by the balance between caloric intake and expenditure. In contrast, less is known about the mechanisms that regulate the qualitative aspects of feeding, although they also significantly impact the control of weight and health. However, two aspects of feeding quality relevant to weight loss and weight regain are discussed in this review: macronutrient-based diet selection (what) and feeding pattern (when). This review covers the importance of these two factors in controlling weight and health, and the central mechanisms that regulate them. The relatively limited and fragmented knowledge on these topics indicates that we lack an integrated understanding of the qualitative aspects of feeding behavior. To promote better understanding of weight control, research efforts must focus more on the mechanisms that control the quality and quantity of feeding behavior. This understanding will contribute to improving dietary interventions for achieving weight control and for preventing weight regain following weight loss.
The hypothalamus is the principal regulator of body weight and energy balance. It modulates both energy intake and energy expenditure by sensing the energy status of the body through neural inputs ...from the periphery as well as direct humoral inputs. Leptin, an adipokine, is one of the humoral factors responsible for alerting the hypothalamus that enough energy is stored in the periphery. Plasma leptin levels are positively linked to adiposity; leptin suppress energy intake and stimulates energy expenditure. However, prolonged increases in plasma leptin levels due to obesity cause leptin resistance, affecting both leptin access to hypothalamic neurons and leptin signal transduction within hypothalamic neurons. Decreased sensing of peripheral energy status through leptin may lead to a positive energy balance and gradual gains in weight and adiposity, further worsening leptin resistance. Leptin resistance, increased adiposity, and weight gain are all associated with aging in both humans and animals. Central insulin resistance is associated with similar observations. Therefore, improving the action of humoral factors in the hypothalamus may prevent gradual weight gain, especially during middle age. SIRT1 is a NAD(+)-dependent protein deacetylase with numerous substrates, including histones, transcription factors, co-factors, and various enzymes. SIRT1 improves both leptin sensitivity and insulin sensitivity by decreasing the levels of several molecules that impair leptin and insulin signal transduction. SIRT1 and NAD(+) levels decrease with age in the hypothalamus; increased hypothalamic SIRT1 levels prevent age-associated weight gain and improve leptin sensitivity in mice. Therefore, preventing the age-dependent loss of SIRT1 function in the hypothalamus could improve the action of humoral factors in the hypothalamus as well as central regulation of energy balance.
The hypothalamus is the center of controlling food intake and energy expenditure by integrating information on energy status, i.e. adiposity and nutrient signals. Especially, two types of neurons in ...the arcuate nucleus of the hypothalamus, anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons, play vital roles in regulating feeding and energy expenditure. On the other hand, insulin and leptin are hormones that control food intake via regulating POMC and AgRP expression. FoxO1 is a downstream effecter of insulin signaling and Sirt1 is an NAD+-dependent deacetylase, both of which have been reported to play important roles in the regulation of metabolism in various organs including liver, pancreas, muscle, adipose tissue and hypothalamus. Histological analyses revealed that FoxO1 and Sirt1 are expressed in both AgRP and POMC neurons where FoxO1 localizes to the nucleus in the fasted, while to the cytoplasm in the refed condition. In contrast, hypothalamic Sirt1 protein is decreased in the fasted condition due to increased ubiquitination of Sirt1. In rodents, overexpression of FoxO1 in the hypothalamus by adenovirus microinjection induces hyperphagia and body weight gain, and simultaneous overexpression of Sirt1 suppresses these phenotypes. FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of AgRP and POMC through transcriptional squelching, and Sirt1 suppresses AgRP expression. In conclusion, we propose that FoxO1 and Sirt1 in hypothalamus are key regulators of energy homeostasis and are molecular targets for the development of new strategy of treating obesity.
Mitochondria are eukaryotic organelles that consist of outer and inner bilayer membranes with a positive potential (H+) in the intermembrane space. This organelle plays an important role in ATP ...production and apoptosis. To observe the mitochondria in living cells, several fluorescent dyes (such as MitoTracker® a standard mitochondrial imager or rhodamine 123) have been developed. However, these reagents are unstable and exhibit a wide range of emission spectra, thereby hampering double staining results. Using recombinant DNA techniques, green or red fluorescent protein (GFP or RFP)-tagged proteins are now available for multi-color labeling of mitochondria. Here, we have discussed the development of the novel mitochondrial live imagers MitoMM1/2, derivatives of ATTO565; furthermore, MitoMM1/2 are sensitive to the membrane potential, resistant to detergents, and the fluorescence of MitoMM1/2 does not overlap with green fluorescence.
•MitoMM1/2 are new mitochondrial live imagers that ensure ease of operation.•MitoMM1/2 provide a narrow emission spectrum without overlapping with green emission.•MitoMM1/2 signals are resistance to detergents.
Aim: The ring finger protein 213 gene (RNF213) p.R4810K variant is a major susceptibility gene for intracranial arterial stenosis in East Asia. We hypothesized that if intracranial arterial stenosis ...is induced by a non-atherosclerotic mechanism similar to moyamoya disease, the patients with RNF213 p.R4810K variant may have a lower cumulative atherosclerotic burden than the non-carriers.Methods: A total of 112 participants with intracranial arterial stenosis were enrolled in this multicenter cross-sectional study. We compared the prevalence of atherosclerotic risk factors and three different cardiovascular risk scores (Essen Stroke Risk Score, Framingham Risk Score, and Suita Risk Score) between the RNF213 p.R4810K variant carriers and non-carriers. Patients with moyamoya disease were excluded from the study.Results: The RNF213 p.R4810K variant carriers were younger than the non-carriers (P＜0.001). The prevalence of each atherosclerotic risk factor was not significant, but it tended to be lower in the variant carriers. The Essen Stroke Risk Score (carriers: 2.3±1.5 vs. non-carriers: 2.9±1.5, P=0.047), Framingham Risk Score (10.7±6.4 vs. 15.3±6.2, P=0.001), and Suita Risk Score (35.4±15.8 vs. 48.7±15.2, P＜0.001) were significantly lower in the variant carriers. Among the three risk scores, the Suita score showed the highest predictive accuracy for the variant carriers.Conclusions: RNF213 p.R4810K variant carriers have a lower cumulative atherosclerotic burden than non-carriers among patients with intracranial arterial stenosis. New therapeutic approaches beyond the standard management of atherosclerotic risk factors are required to prevent the development of intracranial arterial stenosis.
Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive ...thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33
mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33
dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)
receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33
DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.
The association between cancer survivors and stroke deaths remains unclear. We aimed to evaluate the risk of fatal stroke in patients with cancer.
This study was conducted using data from the Osaka ...Cancer Registry and vital statistics in Japan, collected from 1985 to 2013. We extracted patient data and investigated the causes of death. Standardized mortality ratios were calculated to compare the risk of stroke in patients with cancer to that in the general population. Poisson regression models were used to estimate the risk of stroke in patients with cancer and other cancer subgroups. Stroke types were used for risk stratification.
We identified 688,473 eligible patients with cancer. The cohort contributed 2,668,126 person-years at risk. During the study period, 337,117 patients died; stroke was the cause of death in 5496 patients. Stroke types included cerebral infarction (3259), intracerebral hemorrhage (1539), subarachnoid hemorrhage (364), and other cerebrovascular diseases (334). The crude mortality rate from fatal stroke was 205.99 per 100,000 person-years. The standardized mortality ratio (95 % confidence interval) for fatal stroke was 1.75 (1.71–1.80). When stratified by stroke types, the ratios for cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage were 1.83 (1.76–1.89), 2.38 (2.26–2.50), and 2.28 (2.03–2.56), respectively. The risk of fatal stroke increased with time after cancer diagnosis. The multivariate Poisson regression model indicated that men were more likely to die of stroke than women.
Cancer survivors have a higher risk of fatal stroke than the general population across all stroke types.
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•The risk of fatal stroke in cancer survivors remains unclear.•Cancer survivors have a significant high risk of death from stroke.•The risks varied by cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage.•Careful follow-up for cancer survivors in clinical practice is required.•The risk of fatal stroke among cancer survivors has decreased in recent years.
The cluster of differentiation 36 (CD36) is a transmembrane receptor expressed in various cells and has diverse lipid ligands. The expression of CD36 in the murine olfactory epithelium and its ...ability to recognize certain species of fatty aldehydes, a class of odor-active volatile compounds, have suggested a role for this receptor in the capture of specific odorants in the nasal cavity of mammals. However, the spectrum of CD36-recognizable volatile compounds is poorly understood. In this study, we employed our recently devised assay with fluorescently labeled peptides as probes (fluorescence intensity assay) and identified distinct fatty acetates as volatile compounds that bind specifically to amino acid region 149-168 of CD36 (eg dodecyl and tetradecyl acetates). The present findings demonstrate the utility of our assay for the discovery of novel CD36 ligands and support the notion that the receptor functions as a captor of volatile compounds in the mammalian olfactory system.
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