We often think of bones as immobile structures, but scientists are learning that bones are far more dynamic than once believed. Research has shown that they play important roles in immunity, kidney health, and metabolism. In a recent study, Dr. Stavroula Kousteni, Associate Professor at Columbia University Medical Center, led her team to the discovery that lipocalin 2, a hormone secreted by bone cells, suppresses appetite in mice. The study findings will potentially add to the understanding of weight management and maintaining a healthy metabolism and also raise questions about the possibility of other bone-derived hormones and what their potential functions could be.
Previously, it was thought that lipocalin 2 was only secreted by adipose tissue and contributed to obesity. Using genetically modified mice, Dr. Kousteni and her team showed lipocalin 2 levels were tenfold higher in osteoblasts (the bone forming cells) versus fat. In mice that were engineered to lack lipocalin 2 in fat cells or osteoblasts, the investigators found that only mice lacking lipocalin 2 in the osteoblasts had increased food intake, body weight, and impaired glucose metabolism. In normal mice and in obese leptin-receptor deficient mice, administration of lipocalin 2 suppressed appetite, decreased body weight and improved glucose metabolism.
The brain controls feeding behavior. The Kousteni team demonstrated that lipocalin 2 crosses the blood-brain barrier and binds to the melanocortin 4 receptor, (which is linked to feeding behavior) in the neurons of the hypothalamus, thereby activating appetite-suppressing pathways in the brain. This shows at least in mice, that control of appetite is, in part, an endocrine function of the bone. The study findings could lead to the development of new treatments for obesity, type 2 diabetes, and other metabolic disorders. Interestingly, type ll diabetic patients with higher lipocalin 2 levels had lower body weight and glycated hemoglobin levels, the latter being a measure of glucose control.
“In recent years, studies at CUMC and elsewhere have shown that bone is an endocrine organ and produces hormones that affect brain development, glucose balance, kidney function, and male fertility,” says Dr. Kousteni. “Our findings add a critical new function of bone hormones to this list—appetite suppression—which may open a wholly new approach to the treatment of metabolic disorders.”¹
¹ “Bone-Derived Hormone Suppresses Appetite in Mice.” Columbia University Medical Center Newsroom. Columbia University Medical Center, 08 Mar. 2017. Web.
Our work at the Orentreich Foundation for the Advancement of Science has proven that methionine restriction (MR) extends lifespan and has many beneficial effects on various systems in animal models. Rodent MR models have shown improved cardiovascular function, bone development, insulin sensitivity, stress tolerance, and glucose metabolism, as well as a reduction in body mass and cancer development. Some of these effects have also been documented in invertebrate organisms, such as yeast, nematodes, and fruit flies.
In order for these effects to translate to humans, it is crucial to have access to the appropriate food sources. Building on their previous research, Associate Science Director Gene Ables and Senior Scientist Jay Johnson utilized information from the US National Nutrient Database to compile a list of various food sources that contain methionine content in order to give individuals an idea of what foods are best for a low-methionine diet. It was revealed that food sources for beef contained the highest content of methionine, followed by other animal-based sources such as poultry, fish, and dairy, whereas food like nuts, vegetables, cereals, and fruit contained less methionine. According to the data found, in order to achieve MR, a person has to eat more plant-based food and less animal-based food. This supports the idea that a vegan diet, which is naturally low in methionine, could be beneficial to healthspan.
Ables GP, Johnson JE
Exp. Gerontol. 2017 Jan;
Methionine restriction (MR) extends lifespan across different species. The main responses of rodent models to MR are well-documented in adipose tissue (AT) and liver, which have reduced mass and improved insulin sensitivity, respectively. Recently, molecular mechanisms that improve healthspan have been identified in both organs during MR. In fat, MR induced a futile lipid cycle concomitant with beige AT accumulation, producing elevated energy expenditure. In liver, MR upregulated fibroblast growth factor 21 and improved glucose metabolism in aged mice and in response to a high-fat diet. Furthermore, MR also reduces mitochondrial oxidative stress in various organs such as liver, heart, kidneys, and brain. Other effects of MR have also been reported in such areas as cardiac function in response to hyperhomocysteinemia (HHcy), identification of molecular mechanisms in bone development, and enhanced epithelial tight junction. In addition, rodent models of cancer responded positively to MR, as has been reported in colon, prostate, and breast cancer studies. The beneficial effects of MR have also been documented in a number of invertebrate model organisms, including yeast, nematodes, and fruit flies. MR not only promotes extended longevity in these organisms, but in the case of yeast has also been shown to improve stress tolerance. In addition, expression analyses of yeast and Drosophila undergoing MR have identified multiple candidate mediators of the beneficial effects of MR in these models. In this review, we emphasize other in vivo effects of MR such as in cardiovascular function, bone development, epithelial tight junction, and cancer. We also discuss the effects of MR in invertebrates.
Plummer J, Park M, Perodin F, Horowitz MC, Hens JR
J. Cell. Biochem. 2016 May;
Dietary methionine restriction (MR) increases longevity and improves healthspan in rodent models. Young male C57BL/6J mice were placed on MR to assess effects on bone structure and formation. Mice were fed diets containing 0.86% or 0.12% methionine for 5 weeks. Fasting blood plasma was analyzed for metabolic and bone-related biomarkers. Tibiae were analyzed by histomorphometry, while femurs were analyzed by micro-CT and biomechanically using 4-point bending. MR mice had reduced plasma glucose and insulin, while FGF21 and FGF23 increased. Plasma levels of osteocalcin and osteoprotegrin were unaffected, but sclerostin and procollagen I decreased. MR induced bone marrow fat accretion, antithetical to the reduced fat depots seen throughout the body. Cortical bone showed significant decreases in Bone Tissue Density (BTD). In trabecular bone, mice had decreased BTD, bone surface, trabecula and bone volume, and trabecular thickness.. Biomechanical testing showed that on MR, bones were significantly less stiff and had reduced maximum load and total work, suggesting greater fragility. Reduced expression of RUNX2 occurred in bone marrow of MR mice. These results suggest that MR alters bone remodeling and apposition. In MR mice, miR-31 in plasma and liver, and miR-133a, miR-335-5p, and miR-204 in the bone marrow was elevated. These miRNAs were shown previously to target and regulate Osterix and RUNX2 in bone, which could inhibit osteoblast number and function. Therefore, dietary MR in young animals alters bone structure by increasing miRNAs in bone and liver that can target RUNX2. This article is protected by copyright. All rights reserved.