The study is published Sept. 24 online ahead of print in the journal Cell Reports.
“We have found that the level of your hunger could determine your bone structure,” said one of the senior authors, Tamas L. Horvath, the Jean and David W. Wallace Professor of Comparative Medicine, and professor of neurobiology and obstetrics, gynecology, and reproductive sciences. Horvath is also director of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.
“The less hungry you are, the lower your bone density, and surprisingly, the effects of these neurons on bone mass are independent of the effect of the hormone leptin on these same cells.”
Horvath and his team focused on agouti-related peptide (AgRP) neurons in the hypothalamus, which control feeding and compulsive behaviors. Using mice that were genetically-engineered so their cells selectively interfere with the AgRP neurons, the team found that these same cells are also involved in determining bone mass.
The team further found that when the AgRP circuits were impaired, this resulted in bone loss and osteopenia in mice — the equivalent of osteoporosis in women. But when the team enhanced AgRP neuronal activity in mice, this actually promoted increased bone mass.
“Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin’s action,” said co-senior author Karl Insogna, M.D., professor of medicine, and director of the Yale Bone Center. “Based on our findings, it seems that the effect of AgRP neurons on bone metabolism in adults is mediated at least in part by the sympathetic nervous system, but more than one pathway is likely involved.”
“There are other mechanisms by which the AgRP system can affect bone mass, including actions on the thyroid, adrenal and gonad systems,” Insogna added. “Further studies are needed to assess the hormonal control of bone metabolism as a pathway modulated by AgRP neurons.”
Other authors on the study include Jae Geun Kim, Ben-Hua Sun, Marcelo O. Dietrich, Marco Koch, Gang-Qing Yao, and Sabrina Diano.
Funding: The study was supported by the National Institutes of Health, a Core Center award, and an ADA mentored Fellowship Award.
Source: Karen N. Peart – Yale
Image Source: The image is credited to Michael Helfenbein, Yale University
Original Research: Full open access research for “AgRP Neurons Regulate Bone Mass” by Jae Geun Kim, Ben-Hua Sun, Marcelo O. Dietrich, Marco Koch, Gang-Qing Yao, Sabrina Diano, Karl Insogna, and Tamas L. Horvath in Cell Reports. Published online September 24 2015 doi:10.1016/j.celrep.2015.08.070
AgRP Neurons Regulate Bone Mass
•Impaired AgRP neurons cause bone loss
•Enhanced AgRP neuronal activity increases bone mass
•Leptin receptors in AgRP neurons do not affect bone mass
The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1−/−), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1−/− mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action.
“AgRP Neurons Regulate Bone Mass” by Jae Geun Kim, Ben-Hua Sun, Marcelo O. Dietrich, Marco Koch, Gang-Qing Yao, Sabrina Diano, Karl Insogna, and Tamas L. Horvath in Cell Reports. Published online September 24 2015 doi:10.1016/j.celrep.2015.08.070
Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brainby the AgRP/NPY neuron. It is synthesised only in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.
AgRP is a paracrine signalling molecule made up of 112 amino acids (the gene product of 132 amino acids is processed by removal of the N-terminal 20-residue signal peptide domain). It was independently identified by two teams in 1997 based on its sequence similarity with agouti signalling peptide (ASIP), a protein synthesised in the skin that controls coat colour. AgRP is approximately 25% identical to ASIP. The murine homologue of AgRP consists of 111 amino acids (precursor is 131 amino acids) and shares 81% amino acid identity with the human protein. Biochemical studies indicate AgRP to be very stable to thermal denaturation and acid degradation. Its secondary structure consists mainly of random coils and β-sheets that fold into an inhibitor cystine knot motif. AGRP maps to human chromosome 16q22 and Agrp to mouse chromosome 8D1-D2.
Agouti-related protein is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with lower levels of expression in the testis, kidneys, and lungs. The appetite-stimulating effects of AgRP are inhibited by the hormone leptin and activated by the hormone ghrelin. Adipocytes secrete leptin in response to food intake. This hormone acts in the arcuate nucleus and inhibits the AgRP/NPY neuron from releasing orexigenic peptides.
Ghrelin has receptors on NPY/AgRP neurons that stimulate the secretion of NPY and AgRP to increase appetite. AgRP is stored in intracellular secretory granules and is secreted via a regulated pathway. The transcriptional and secretory action of AgRP is regulated by inflammatory signals. Levels of AgRP are increased during periods of fasting. It has been found that AgRP stimulates the hypothalamic-pituitary-adrenocortical axis to release ACTH, cortisol and prolactin.
It also enhances the ACTH response to IL-1-beta, suggesting it may play a role in the modulation of neuroendocrine response to inflammation.Conversely, AgRP-secreting neurons inhibit the release of TRH from the PVN, which may contribute to conservation of energy in starvation. This pathway is part of a feedback loop, since TRH-secreting neurons from PVN stimulate AgRP neurons.
AGRP has been demonstrated to be an inverse agonist of melanocortin receptors, to be specific MC3-R and MC4-R. The melanocortin receptors, MC3-R and MC4-R, are directly linked to metabolism and body weight control. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone) and antagonized by the agouti-related protein. Whereas α-MSH acts broadly on most members of the MCR family (with the exception of MC2-R), AGRP is highly specific for only MC3-R and MC4-R. This inverse agonism not only antagonizes the action of melanocortin agonists such as α-MSH but also further decreases the cAMP produced by the affected cells. The exact mechanism by which AgRP inhibits melanocortin-receptor signalling is not completely clear.
It has been suggested that Agouti-related protein binds MSH receptors and acts as a competitive antagonist of ligand binding. Studies of Agouti protein in B16 melanoma cells supported this logic. The expression of AgRP in the adrenal gland is regulated by glucocorticoids. The protein blocks α-MSH-induced secretion of corticosterone.
Orthologs of AgRP, ASIP, MCIR, and MC4R have been found in mammalian, teleost fish, and avian genomes. This suggests that the agouti-melanocortin system evolved by gene duplication from individual ligand and receptor genes in the last 500 million years.
Role in Obesity
AgRP induces obesity by chronic antagonism of the MC4-R. Overexpression of AgRP in transgenic mice (or intracerebroventricular injection) causes hyperphagia and obesity, whilst AgRP plasma levels have been found to be elevated in obese human males. Understanding the role AgRP plays in weight gain may assist in developing pharmaceutical models for treating obesity.
AgRP mRNA levels have been found to be down regulated following an acute stressful event.
Studies suggest that systems involved in the regulation of stress response and of energy balance are highly integrated.
Loss or gain of AgRP function may result in inadequate adaptive behavioural responses to environmental events, such as stress, and have potential to contribute to the development of eating disorders.
It has been shown that polymorphisms in the AgRP gene have been linked with anorexia nervosa as well as obesity.
Some studies suggest that inadequate signalling of AgRP during stress may result in binge eating.
Starvation-induced hypothalamic autophagy generates free fatty acids, which in turn regulate neuronal AgRP levels.
About the pituitary gland
The pituitary gland is a small gland located near the brain. This gland is often referred to as the “master endocrine gland” because it releases hormones that affect many bodily functions. The pituitary gland is controlled by the hypothalamus, a small structure also near the brain that is connected to the pituitary gland.
A pituitary gland has 2 lobes, the anterior, or front, and the posterior, or back. Each lobe is responsible for releasing specific hormones. These different hormones include:
Anterior pituitary lobe hormones
- Thyroid stimulating hormone (TSH) stimulates the thyroid gland, which helps regulate the body’s metabolism.
- Adrenocorticotrophic hormone (ACTH) controls the hormones released by the adrenal gland, which supports blood pressure, metabolism, and the body’s response to stress.
- Gonadotropins, a family of hormones that include follicle stimulating hormone (FSH) and luteinizing hormone (LH), stimulate production of sperm in a man’s testicles or eggs in a woman’s ovaries. Gonadotropins also regulate a woman’s menstrual cycle.
- Growth hormone promotes growth of the long bones in the arms and legs, and thickens the skull and bones of the spine. The hormone also causes the tissue over the bones to thicken.
- Prolactin stimulates milk production in women after childbirth. Prolactin is also found in men.
- Lipotropin stimulates the movement of fat from the body to the bloodstream.
- Melanocyte stimulating hormone (MSH) regulates the production of melanin, the pigment in skin.
Posterior pituitary lobe hormones
- Oxytocin stimulates contraction of the uterus during childbirth and the flow of milk during breastfeeding.
- Antidiuretic hormone, also known as vasopressin, increases reabsorption of water by the kidneys and allows a person to stay hydrated.
Hypothalamus is a region of the forebrain below the thalamus that coordinates both the autonomic nervous system and the activity of the pituitary, controlling body temperature, thirst, hunger, and other homeostatic systems, and involved in sleep and emotional activity.
Pituitary gland tumor
People with a pituitary gland tumor may experience the following symptoms or signs. Sometimes, people with a pituitary gland tumor do not have any of these changes. Or, the cause of a symptom may be another medical condition that is not a pituitary gland tumor.
- Vision problems
- Changes in menstrual cycles in women
- Impotence, which is the inability to achieve or maintain an erection in men and is caused by hormone changes
- Infertility, meaning the inability to have children
- Inappropriate production of breast milk
- Cushing’s syndrome, a combination of weight gain, high blood pressure, diabetes, and easy bruising that is caused by overproduction of ACTH
- Acromegaly, the enlargement of the extremities or limbs and thickening of the skull and jaw caused by too much growth hormone
- Unexplained tiredness
- Mood changes