That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to ...improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify
, an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.
Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early ...during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.
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•Bone via the hormone osteocalcin improves muscle function during exercise•Circulating osteocalcin levels decrease in aging mice, monkeys, and humans•Osteocalcin promotes muscle uptake and utilization of glucose and fatty acids•Osteocalcin promotes muscle IL-6 secretion during exercise
Mera et al. show that the bone-derived hormone osteocalcin is necessary for optimum exercise capacity and that this hormone decreases with aging in mice, monkeys, and humans of both genders. Osteocalcin promotes muscle uptake and utilization of glucose and lipids during exercise and greatly improves the exercise capacity of old mice.
Like many other organs, bone can act as an endocrine organ through the secretion of bone-specific hormones or "osteokines." At least two osteokines are implicated in the control of glucose and energy ...metabolism: osteocalcin (OCN) and lipocalin-2 (LCN2). OCN stimulates the production and secretion of insulin by the pancreatic β-cells, but also favors adaptation to exercise by stimulating glucose and fatty acid (FA) utilization by the muscle. Both of these OCN functions are mediated by the G-protein-coupled receptor GPRC6A. In contrast, LCN2 influences energy metabolism by activating appetite-suppressing signaling in the brain. This action of LCN2 occurs through its binding to the melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVN) and ventromedial neurons of the hypothalamus.
Abstract Objective A decrease in muscle protein turnover and therefore in muscle mass is a hallmark of aging. Because the circulating levels of the bone-derived hormone osteocalcin decline steeply ...during aging in mice, monkeys and humans we asked here whether this hormone might regulate muscle mass as mice age. Methods We examined muscle mass and strength in mice lacking osteocalcin ( Ocn −/−) or its receptor in all cells ( Gprc6a −/−) or specifically in myofibers ( Gprc6a Mck −/−) as well as in 9 month-old WT mice receiving exogenous osteocalcin for 28 days. We also examined protein synthesis in WT and Gprc6a −/− mouse myotubes treated with osteocalcin. Results We show that osteocalcin signaling in myofibers is necessary to maintain muscle mass in older mice in part because it promotes protein synthesis in myotubes without affecting protein breakdown. We further show that treatment with exogenous osteocalcin for 28 days is sufficient to increase muscle mass of 9-month-old WT mice. Conclusion This study uncovers that osteocalcin is necessary and sufficient to prevent age-related muscle loss in mice.
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The current obesity epidemic is a major worldwide health and economic burden. In the modern environment, an increase in the intake of high-fat and high-sugar foods plays a crucial ...role in the development of obesity by disrupting the mechanisms governing food intake and energy balance. Food intake and whole-body energy balance are regulated by the central nervous system through a sophisticated neuronal network located mostly in the hypothalamus. In particular, the hypothalamic arcuate nucleus (ARC) is a fundamental center that senses hormonal and nutrient-related signals informing about the energy state of the organism. The ARC contains two small, defined populations of neurons with opposite functions: anorexigenic proopiomelanocortin (POMC)-expressing neurons and orexigenic Agouti-related protein (AgRP)-expressing neurons. AgRP neurons, which also co-produce neuropeptide Y (NPY) and γ-Aminobutyric acid (GABA), are involved in an increase in hunger and a decrease in energy expenditure. In this review, we summarize the key findings from the most common animal models targeting AgRP neurons and the tools used to discern the role of this specific neuronal population in the control of peripheral metabolism, appetite, feeding-related behavior, and other complex behaviors. We also discuss how knowledge gained from these studies has revealed new pathways and key proteins that could be potential therapeutic targets to reduce appetite and food addictions in obesity and other diseases.
Mitochondrial fatty acid oxidation in obesity Serra, Dolors; Mera, Paula; Malandrino, Maria Ida ...
Antioxidants & redox signaling,
07/2013, Letnik:
19, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Current lifestyles with high-energy diets and little exercise are triggering an alarming growth in obesity. Excess of adiposity is leading to severe increases in associated pathologies, such as ...insulin resistance, type 2 diabetes, atherosclerosis, cancer, arthritis, asthma, and hypertension. This, together with the lack of efficient obesity drugs, is the driving force behind much research.
Traditional anti-obesity strategies focused on reducing food intake and increasing physical activity. However, recent results suggest that enhancing cellular energy expenditure may be an attractive alternative therapy.
This review evaluates recent discoveries regarding mitochondrial fatty acid oxidation (FAO) and its potential as a therapy for obesity. We focus on the still controversial beneficial effects of increased FAO in liver and muscle, recent studies on how to potentiate adipose tissue energy expenditure, and the different hypotheses involving FAO and the reactive oxygen species production in the hypothalamic control of food intake.
The present review aims to provide an overview of novel anti-obesity strategies that target mitochondrial FAO and that will definitively be of high interest in the future research to fight against obesity-related disorders.
Exercise is an evolutionary conserved survival function that nowadays has beneficial health effects. The increased metabolic activity of contracting skeletal muscle affects the biology of many organs ...involved in regulating muscle functions. The discovery of hormones and cytokines secreted by bone and skeletal muscle during exercise, has recently added experimental credence to the notion that a crosstalk exists between these organs. Bone through the hormone osteocalcin, promotes exercise capacity in the mouse. After binding to a G-coupled protein receptor, Gprc6a, osteocalcin increases nutrients uptake and catabolism in myofibers during exercise. The catabolic aspect of osteocalcin distinguishes it from insulin signaling. In addition, osteocalcin regulates the endocrine function of skeletal muscle because it enhances the expression of interleukin-6 (IL-6). IL-6 is produced and secreted by contracting skeletal muscle and exerts autocrine, paracrine and systemic effects. One of the systemic functions of IL-6 is to drive the generation of bioactive osteocalcin. Altogether, these studies have revealed a feed-forward loop between bone and skeletal muscle that are necessary and sufficient for optimum exercise capacity. This endocrine regulation of exercise biology, suggest novel and adapted strategies for the prevention or treatment of age related muscle loss.
Cleidocranial dysplasia (CCD) is an autosomal dominant human disorder characterized by abnormal bone development that is mainly due to defective intramembranous bone formation by osteoblasts. Here, ...we describe a mouse strain lacking the E3 ubiquitin ligase RNF146 that shows phenotypic similarities to CCD. Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of WNT3a-induced β-catenin activation and reduced Fgf18 expression in osteoblasts. We show that FGF18 induces transcriptional coactivator with PDZ-binding motif (TAZ) expression, which is required for osteoblast proliferation and differentiation through transcriptional enhancer associate domain (TEAD) and runt-related transcription factor 2 (RUNX2) transcription factors, respectively. Finally, we demonstrate that adipogenesis is enhanced in Rnf146-/- mouse embryonic fibroblasts. Moreover, mice with loss of RNF146 within the osteoblast lineage had increased fat stores and were glucose intolerant with severe osteopenia because of defective osteoblastogenesis and subsequent impaired osteocalcin production. These findings indicate that RNF146 is required to coordinate β-catenin signaling within the osteoblast lineage during embryonic and postnatal bone development.
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Brown adipose tissue (BAT) is raising high expectations as a potential target in the fight against metabolic disorders such as obesity and type 2 diabetes. BAT utilizes fuels such as ...fatty acids to maintain body temperature by uncoupling mitochondrial electron transport to produce heat instead of ATP. This process is called thermogenesis. BAT was considered to be exclusive to rodents and human neonates. However, in the last decade several studies have demonstrated that BAT is not only present but also active in adult humans and that its activity is reduced in several pathological conditions, such as aging, obesity, and diabetes. Thus, tremendous efforts are being made by the scientific community to enhance either BAT mass or activity. Several activators of thermogenesis have been described, such as natriuretic peptides, bone morphogenic proteins, or fibroblast growth factor 21. Furthermore, recent studies have tested a therapeutic approach to directly increase BAT mass by the implantation of either adipocytes or fat tissue. This approach might have an important future in regenerative medicine and in the fight against metabolic disorders. Here, we review the emerging field of BAT transplantation including the various sources of mesenchymal stem cell isolation in rodents and humans and the described metabolic outcomes of adipocyte cell transplantation and BAT transplantation in obesity.
C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we ...synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (−)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis. In addition, central and peripheral administration of (+)-UB006 or (−)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (−)-UB006 that has no anorexigenic side effects.
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•(−)-UB006 is a new synthetized product that inhibits fatty acid synthase activity and displays a potent cytotoxic effect.•(−)-UB006 cytotoxic effect involves mechanisms that reduces fatty acid synthesis, energy production and activates apoptosis.•In vivo, (−)-UB006 do not affect food intake and body weight.•Therefore (−)-UB006 could be used as a potential anticancer drug.
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