questions will be uploaded in a word doc
Unit 8 Assignment (25 points) There are many signaling molecules that regulate short-term and long-term appetite and body weight. After completing this unit’s reading, select one molecule that is known to suppress appetite and one that is known to stimulate appetite. You may find the figures below helpful. Please be specific in your response and make sure to use your own words as this assignment will undergo originality check. 1. Select one signaling molecule that is known to suppress appetite. a. What is the name of the signaling molecule? [2 pts] b. Which organ or tissue releases this signaling molecule? (there may be more than one organ/tissue) [2 pts] c. Which organ or tissue responds to this signal? (there may be more than one organ/tissue) [2 pts] d. What is the biological response to this signal? What does the body do in response to the signal? [4 pts] 2. Select one signaling molecule that is known to stimulate appetite. a. What is the name of the signaling molecule? (2 pt) b. Which organ or tissue releases this signaling molecule? (there may be more than one organ/tissue) [2 pts] c. Which organ or tissue responds to this signal? (there may be more than one organ/tissue) [2 pts] d. What is the biological response to this signal? What does the body do in response to the signal? [4 pts] 3. a. Which regions of the hypothalamus in the human brain are particularly important in appetite and body weight regulation? Select at least two. [2 pts] b. What happens when those regions are electrically stimulated or lesioned in experimental studies? [3 pts] Dis Model Mech. 2017 Jun 1; 10(6): 679–689. doi: 10.1242/dmm.026609: 10.1242/dmm.026609 PMCID: PMC5483000 PMID: 28592656 Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity Katharina Timper and Jens C. Brüning Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, Cologne 50931, Germany Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 26, Cologne 50924, Germany Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, Cologne 50931, Germany National Center for Diabetes Research (DZD), Ingolstädter Land Str. 1, Neuherberg 85764, Germany Author for correspondence (bruening@sf.mpg.de) Copyright © 2017. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. ABSTRACT The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. KEY WORDS: Obesity, Type 2 diabetes mellitus, Glucose homeostasis, Hypothalamus, CNS Introduction 1,2,3 1,2,3,4,* 1 2 3 4 * https://www.ncbi.nlm.nih.gov/pubmed/28592656 https://www.ncbi.nlm.nih.gov/pubmed/?term=Timper%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28592656 https://www.ncbi.nlm.nih.gov/pubmed/?term=Br%26%23x000fc%3Bning%20JC%5BAuthor%5D&cauthor=true&cauthor_uid=28592656 mailto:dev@null https://www.ncbi.nlm.nih.gov/pmc/about/copyright/ http://creativecommons.org/licenses/by/3.0 The number of overweight and obese people worldwide has increased over recent years, giving rise to a global obesity epidemic. According to the World Health Organization (WHO), in 2014, more than 1.9 billion adults were overweight, of which over 600 million were classified as clinically obese (WHO, 2015). Perhaps even more alarmingly, 42 million children under the age of 5 were overweight or obese in 2013 (WHO, 2015). Obesity is a major risk factor for associated comorbidities such as cardiovascular diseases (Kim et al., 2015), type 2 diabetes mellitus, cancer (Calle et al., 2003) and musculoskeletal disorders, and is associated with an increased overall mortality relative to non-obese individuals (Adams et al., 2006). Obesity results from the dysregulation of energy metabolism (Crowley et al., 2002). The central nervous system (CNS) plays a key role in sensing and controlling the energy status of the organism (Myers and Olson, 2012), and the hypothalamus in particular has emerged as an integrating, superordinate master regulator of whole-body energy homeostasis. Obesity has long been considered to be the result of a lack of discipline and effort to reduce calorie intake and to increase physical activity, which has led to a fundamental and still present social weight-related stigmatization of affected individuals (Friedman, 2004). However, extensive research in both humans and various murine model systems over recent decades has revealed that a complex interplay of genes and environmental factors that impact CNS control of food intake and energy homeostasis pave the way for the development of obesity. In this review and its accompanying poster, we provide a snapshot of the hypothalamic neurocircuits that regulate the homeostatic control of energy metabolism and feeding. We also give an overview of the pleiotropic factors involved in the regulation and dysregulation of the homeostatic hypothalamic system in the context of obesity, including hypothalamic inflammation as well as insulin and leptin resistance. Later, we discuss the impact of a maternal high-fat diet and obesity on offspring and highlight the importance of mitochondrial dynamics and genetic factors involved in the development of obesity at the level of the hypothalamic neurocircuits. Thereby, most of the molecular insights summarized in this article are derived from studies in rodent model organisms. Finally, we provide our outlook on recent perspectives on CNS-dependent control of feeding behavior and metabolism, and future therapeutic approaches to tackle dysfunctional regulation of central energy homeostasis. Hypothalamic neuronal circuits controlling feeding behavior and energy homeostasis Key hypothalamic nuclei The hypothalamus is one of the best-studied and most important brain regions involved in the central control of feeding and energy expenditure. In particular, the arcuate nucleus (ARC) within the hypothalamus is critical for the regulation of feeding and metabolism (Myers and Olson, 2012). The ARC is located near to the median eminence (ME; see poster), a circumventricular organ that is rich in fenestrated capillaries that lead to a ‘leaky’ blood-brain barrier (BBB). The ME facilitates transport of peripheral hormonal and nutrient signals and their sensing by the ARC neurons (Rodríguez et al., 2010). Thereby, the ARC integrates hormonal and nutritional metabolic signals from the peripheral circulation as well as peripheral and central neuronal inputs to generate a coordinated feedback response. There are two distinct, functionally antagonistic types of neurons in the ARC: the orexigenic (appetite- stimulating) neuropeptide Y (NPY) and agouti-related peptide (AgRP)-expressing AgRP/NPY neurons and the anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC)-expressing POMC neurons (see poster) (Gropp et al., 2005; Balthasar et al., 2005). POMC neurons project mainly to second-order neurons in the paraventricular hypothalamic nucleus (PVN), but also to the dorsomedial hypothalamus (DMH), the lateral hypothalamus (LH) and the ventromedial hypothalamus (VMH) (see poster) (Kleinridders et al., 2009; Waterson and Horvath, 2015). These second-order neurons further process the received information and project to multiple neurocircuits outside of the hypothalamus (extrahypothalamic), leading to an integrated response on energy intake and expenditure, respectively (Roh et al., 2016). Neurons within the PVN control sympathetic outflow to peripheral organs (Kannan et al., 1989) and secrete a variety of regulatory neuropeptides (Roh et al., 2016). Destruction of the PVN leads to overeating and obesity (Leibowitz et al., 1981), pointing to the important role of PVN neurons for the inhibitory control of food intake. Moreover, destruction of the VMH results in hyperphagia and obesity (Shimizu et al., 1987), whereas deletion of the DMH (Bellinger and Bernardis, 2002) and the LH (Milam et al., 1980) produces a hypophagic, lean phenotype. Upon nutrient ingestion, POMC is cleaved to α-melanocyte-stimulating hormone (α-MSH) which is released from POMC-axons to activate melanocortin 3 and 4 receptors (MC3/4R) on downstream neurons, including neurons in the PVN (see poster; Healthy postprandial or feeding state), resulting in a decrease in food intake and an increase in energy expenditure (Könner et al., 2009). Although MC4R expression is widely distributed among different brain regions (Gantz et al., 1993a,b; Liu et al., 2003), within the hypothalamus, the PVN displays the highest MC4R expression and is considered to host the predominant energy-intake-regulating MC4R population within the CNS (see Tao, 2010; Krashes et al., 2016 for reviews). Consistent with this, studies in mice have shown that disruption of the MC4R, and specifically in the PVN, results in obesity as a result of hyperphagia and reduced energy expenditure, along with deteriorations in glucose homeostasis (Huszar et al., 1997; Balthasar et al., 2005). Downstream mediators likely to be involved in transducing the effects of MC4R activation on food intake regulation are brain- derived neurotrophic factor (BDNF) (Xu et al., 2003; Nicholson et al., 2007), corticotropin-releasing hormone (CRH) (Lu et al., 2003) and thyrotropin-releasing hormone (TRH) (Fekete et al., 2000; Kim et al., 2000). While food intake is believed to be inhibited via hypothalamic melanocortinergic neurons in a constant manner (Fan et al., 1997), energy expenditure is increased upon MC4R activation due to an increased activity of the sympathetic nervous system leading to brown adipose tissue (BAT) activation (Ste Marie et al., 2000; Voss-Andreae et al., 2007). Fasting, on the other hand, induces the activation of AgRP/NPY neurons that project also to the PVN and the LH (see poster; Healthy fasting state) (Betley et al., 2013). AgRP/NPY neurons co-release NPY and AgRP. NPY directly stimulates food intake (Stanley and Leibowitz, 1984; Clark et al., 1984) via activation of NPY Y1 (Yokosuka et al., 1999) and Y5 (Parker et al., 2000; Cabrele et al., 2000; McCrea et al., 2000) receptors. Furthermore, NPY reduces energy expenditure via a Y1-receptor-mediated reduction