- Email: [email protected]
Metabolic Disease Therapies
Cell Metabolism
Voices Metabolic Disease Therapies In anticipation of our upcoming Cell Symposium on Metabolic Disease Therapies in San Diego, CA, on October 15th–17th (http://cell-symposia.com/metabolic-therapies-2017/), the speakers and organizers share their perspectives on why now, more than ever, cutting-edge research is needed to support effective therapies to combat metabolic disease. Abandoning Conventional Approaches
Surmounting Pitfalls in Translation on the Path to Innovation
Designer Physiology and the Humor in Metabolic Disease
Matthias H. Tscho¨p
Daniel Drucker
Ron Evans
LTRI, Mt. Sinai Hospital
Salk Institute for Biological Studies
Despite a revolution in our understanding of disease pathophysiology, our ability to ameliorate conditions like obesity and NAFLD in the laboratory mouse substantially exceeds our success in translating that knowledge into clinical therapies. Our laboratory, while focused on gut peptides, has been interested in understanding the utility of mouse models as predictors of the therapeutic efficacy of novel metabolic interventions. While mice remain fantastic model organisms for the study of metabolic disease, their suitability as models for chronic metabolic diseases that develop over decades in genetically diverse human subjects has been frequently questioned. More rigor in the replication of studies across species as well as in larger and longer preclinical studies may be a step in the right direction. Enhanced attention to multiple, often profound differences between small laboratory animals and humans with metabolic disease may further sharpen the focus and restrain the rhetoric periodically associated with identification of an important new target, or a ‘‘breakthrough intervention,’’ in a single mouse model studied, often in young mice, over several months. Reassuringly, these caveats are increasingly discussed at scientific meetings, and the level of awareness of translational challenges in the scientific community is slowly but clearly rising. We look forward with enthusiasm to the consideration of new pathways and the development of innovative therapeutic modalities that will make a real difference in arresting the currently rising tsunami of metabolic disease in the years to come.
The study of human physiology dates back to the time of Hippocrates—the Greek physician who developed beliefs on temperament based on earth, water, air, and fire into a medical theory. Each substance had a corresponding humor: black bile, phlegm, blood, and yellow bile, respectively. The underpinning of this brand of Humorism is that endogenous circulating substances act as signals to control bodily function. In the modern era, we can now begin to understand humors, or hormones, as the foundation of physiology: the source of resilience when young and the slouch of frailty as we age. The idea of designer physiology is to use science to manipulate physiology to boost output or function in order to combat the decline associated with aging. Though physiology is inherently adaptive, the generous boundaries of youth become narrowed with age. They become corroded with chronic inflammation, fibrosis, bone loss, weight gain, metabolic disease, Alzheimer’s, and cancer. Knowledge of the molecular architecture of physiologic pathways provides the potential to reactivate a failed or compromised system by rebooting function. The idea of ‘‘resetting’’ physiology has begun with small steps, but its potential is endless. Indeed, the knowledge of any one system is likely to inform us about others. Furthermore, once we understand how to ‘‘game the system,’’ we can begin to generate hybrid or chimeric physiologic pathways and possibly create personalized physiology. What new physiologic function would you like to see invented?
€nchen Helmholtz Zentrum Mu
With their discovery of insulin almost 100 years ago, Frederick Banting and Charles Best turned diabetes from a deadly illness into a chronic disease. Until today, their work has unquestionably represented the most transformative breakthrough within the field of metabolic diseases. While research efforts toward a world without diabetes have steadily increased, both in in number of research efforts and in technical sophistication, so has diabetes incidence and prevalence. Finding a cure rather than incrementally improving manageability of metabolic diseases such as diabetes turns out to be considerably more challenging than expected. Heterogeneity of patient populations and newly uncovered levels of complexity, including epigenetic programming, represent two reasons for the relative lack of novel therapeutics with transformative impact on the pandemic. This Cell Symposium on Metabolic Disease Therapies, therefore, in particular invites scientists to contribute out-of-thebox thinking and discuss unconventional approaches in addition to reporting the latest unpublished advances of existing programs. After 100 years, it may be time to abandon the reliance on conventional approaches and embrace new ideas, even if these are not aligned with established models of metabolic disease pathologies.
Cell Metabolism 26, October 3, 2017 ª 2017 Elsevier Inc. 579
Cell Metabolism
Voices Missing Symbionts?
Inflammometabolism to the Rescue
Mitochondria in Cell Metabolism
Rob Knight
Michael Karin
David Chan
University of California, San Diego
University of California, San Diego
California Institute of Technology
A century ago, complex diseases with effects throughout the body, including the brain, plagued America. The idea that a simple chemical compound could ameliorate a disease as complex as pellagra seemed absurd, and causes were sought in human genetics, food spoilage, and infections. Yet B-complex vitamins in flour, iodine in salt, and vitamin D in milk essentially eliminated these diseases. Today we are faced with dramatic increases in a range of complex chronic diseases—diabetes, Alzheimer’s, asthma, and Parkinson’s are increasing dramatically. What if the underlying causes are as simple as missing nutrients stripped by industrial processing, or missing microbes with which we co-evolved that have been stripped from our bodies by modern antibiotics, delivery and perinatal practices, and separation from the outdoor environment? The prospect of going beyond association studies to truly understand the metabolic effects of our microbial symbionts and the microbiome effects of our metabolites, to truly understand the body at a systems level, excites me tremendously. This is a massive challenge in big data, but advances in technology both to collect the massive datasets and to use increasingly sophisticated computational techniques to extract knowledge from them poise us for a revolution in health in the 21st century as significant as that which occurred in the 20th.
Like all other land-dwelling, multicellular animals, human beings evolved under conditions of periodic and intermittent food supply. Therefore, the ability to store excess calories for a rainy day, or more likely a long period of drought, provides the individual with an obvious evolutionary advantage. Until the so-called ‘‘green revolution,’’ the ability to store excess calories as fat not only under our skin but also within and around our internal organs, especially the liver, was actually beneficial. But nowadays when food is constantly available, excessive lipid storage has become a major health issue. Unfortunately, our understanding of the mechanisms that control lipid biogenesis and metabolism is still sketchy, and such incomplete understanding has hindered therapeutic development. As a result, diseases as common as NAFLD and NASH remain largely untreatable. For many years—and even today—the study of metabolic disease has been in the realm of endocrinology, and endocrinological abnormalities were thought to be the culprit. However, it has become increasingly clear that some of the solutions will come from the fields of inflammation biology and immunology. My own studies and those of others suggest that the immune system, both adaptive and innate, plays a major role in both normal and pathological metabolic regulation. It is my firm belief that the emerging field of immunometabolism will provide us with the new drugs of tomorrow—the blockbusters that will address the medical conditions affecting one-third of humanity.
Considered for decades to be an old science, cell metabolism has again emerged as a timely topic with high relevance to human health and disease. With new technologies enabling a fresh perspective on the biochemicals within cells, there are opportunities to understand how cell metabolism is relevant to diverse biological problems, including aging, stem cell biology, development, and tumorigenesis. As we learn more about these problems, the mitochondrion will undoubtedly constitute a nexus. As the organelles that generate the bulk of cellular ATP through oxidative phosphorylation, mitochondria are clearly central to metabolism. However, oxidative phosphorylation is just the tip of the iceberg—through their functions in intermediary metabolism, apoptosis, calcium handling, iron-sulfur biosynthesis, heme synthesis, and innate immunity, mitochondria impact a surprisingly wide range of cell biology. As with metabolism, the study of mitochondria has undergone a remarkable renaissance, and our appreciation for the complexity and breadth of their cellular functions continues to grow. Mitochondria are no longer the traditional organelles depicted in classical textbooks; they are dynamic organelles whose shape, localization, turnover, and interactions with other organelles change depending on the cellular environment. They are important in all cells, but play particularly important roles in neurons and muscles. As our ideas of metabolism and mitochondria evolve, the challenge will be to devise new therapies to modulate their impact on human diseases.
580 Cell Metabolism 26, October 3, 2017
Cell Metabolism
Voices To Target Mitochondrial Dynamics
Body-Brain Communication
Ground Rules for Behavior
Sabrina Diano
Garret Stuber
Scott Sternson
Yale University School of Medicine
University of North Carolina at Chapel Hill
Janelia Research Campus, HHMI
Almost 20 years ago, we identified mitochondria as a dynamically changing organelle system in hypothalamic neuronal populations that are responsible for feeding and glucose control. We and others went on to show that mitochondrial plasticity and dynamics in neuronal populations are not merely passive responses to the changing functionality of these cells, but actually play crucial roles in enabling proper neuronal responses to changing peripheral cues. Thus, it is highly plausible not only that dynamically changing mitochondrial structure and related function may be relevant for physiological adaptation of brain cells but also that impairment in these processes might be key in the development of metabolic pathologies such as type 2 diabetes (T2D) and other obesity-associated impairments. Thus, targeting emerging molecular drivers of mitochondrial dynamics opens a novel avenue to develop therapeutics to treat metabolic diseases. However, there are both methodological and conceptual roadblocks that need to be conquered in order to make significant advances in these new directions. For example, change in mitochondrial structure and function may vary between different cell and tissue types. It is therefore unlikely that a single approach affecting mitochondrial function in a given direction will benefit the whole organism. In addition, experimental tools to monitor and analyze dynamically changing mitochondrial functions in real time are limited and do not offer analyses of subpopulations of neurons in different parts of the brain. Thus, to target mitochondrial dynamics for therapeutic development of metabolic disorders, these obstacles must be forcefully and directly addressed.
Optimal control of feeding and metabolism requires the brain and other tissues in the body to be in constant communication with each other. Satiety-signaling hormones as well as other factors released from the periphery impact brain function not only to regulate feeding but also to contribute to an individual’s general well-being. Despite a general agreement within the field that hormones and other peripheral signals impact the nervous system to promote appropriate behavioral output, such as food seeking when hungry, the way in which peripheral signals associated with feeding and body weight impact molecularly defined cell types and circuits in the brain remains largely unexplored. In order to continue to push the field forward, we must work to better define, mechanistically, how cells and circuits within the brain are modified by peripheral signals. Additionally, while it is experimentally convenient to study how single hormones impact brain function, metabolic disease is multifaceted: it affects multiple organ systems. Thus, determining how multifactorial changes in hormonal composition may synergistically impact brain function could provide better insight into how metabolic disease impacts the nervous system. By leveraging recent technological advances in mass spectroscopy, single-cell transcriptional profiling, and large-scale calcium imaging of neural network activity, it may soon become possible to identify and prioritize the most promising aspects of body-brain communication to target for next-generation treatments for metabolic diseases.
Brain stimulation control of appetite stands out as one of the most dramatic behavioral responses in neuroscience. I made the leap from synthetic chemistry to the neurobiology of appetite because I became interested in the ‘‘ground rules’’ for motivated behavior. The fact that a localized neuronal activation can elicit complex, goal-direct, motivated behavior provides an entry point to uncovering the clever tricks natural selection employs to ensure that an organism reliably satisfies its needs in an unpredictable world. The answer lies in understanding how complex motivated behaviors associated with survival are embedded in specialized neural circuits. Many challenges have impeded progress in this interesting area: deep and intermingled brain circuits, challenges with quantitatively monitoring physiologic state, and the complexity of behaviors such as food-seeking and consumption. However, improvements in the techniques of deep-brain neuroscience and molecularly defined neural circuitry are putting within reach an understanding of appetite that stretches across all of the length scales of biology, from molecules to neurons, circuits, and behavior. I am confident that our understanding will increase at least 10-fold in the next 10 years. Hopefully, the rapid growth of knowledge about the brain’s control over appetite and metabolism will enable a systematic process to develop safe and effective human therapies for overeating and obesity.
Cell Metabolism 26, October 3, 2017 581
Cell Metabolism
Voices From Genes to Biology
Metabolites and Metabolic Disease
Chemical Evolution of Hormones
Ruth Loos
Barbara B. Kahn, MD
Richard DiMarchi
Icahn School of Medicine at Mount Sinai
Beth Israel Deaconess & Harvard Medical School
Chemistry, Indiana University
Obesity is a complex, multifactorial, and heritable disease. Yet the importance of a genetic contribution is often dismissed, as—many will declare—the obesity epidemic is the consequence of changes in people’s diet and physical activity levels, not in their genome. This is only partially true, however, as it is those who are the most genetically susceptible who gain the most weight in this changing environment. Insight in the genetics of obesity means insight in its underlying biology. Over the past decade, genome-wide screens for obesity have identified hundreds of genetic loci that point to the brain as a key organ in the control of body weight regulation, consistent with observations from monogenic cases of extreme and early onset obesity. A major challenge in the field is translation of these loci into ‘‘tangible’’ genes that can be studied in more experimental settings to get to the bottom of their biology. We try to close the gap between gene discovery and functional follow-up by focusing on more refined phenotypes, such as body fat percentage, specific adipose depots, and biomarkers, and on variants with a high potential to disrupt gene function. It is only once causal genes are identified that we can start thinking about therapeutics, and this requires geneticists and physiologists to work together even more than before.
Reports at the 2002 International Congress on Obesity predicted that this is the first generation in which children will die before their parents. This results from the lifelong burden of obesity, insulin resistance, and T2D emerging in the pediatric population. While recent advances in T2D treatment are substantial, T2D prevalence continues to increase, and many diabetic people are still inadequately treated. To improve outcomes, we need safe insulin-sensitizing medications. Recent technological advances have enabled measurements of thousands of metabolites in biologic samples. ‘‘Signatures’’ of amino acids, fatty acids, and bile acids are being identified in association with obesity and T2D. Interpreting metabolite information presents challenges unlike those encountered with the expansion of genomic data. It is not obvious which metabolite signatures are causes of the metabolic aberrations and which are consequences. What initiates the process, and in which tissues does it start? The roles of dietary nutrients, alterations in pathways that metabolize these nutrients, and gut microbiota need to be determined. We need to understand the mechanisms by which metabolites act as signaling molecules and the functional consequences of metabolite and lipid modification of proteins and cell membrane dynamics. The sheer number of these metabolites, the interconnectedness of their metabolic pathways, and their ability to alter intertissue communication makes this a compelling frontier for understanding metabolic disease and discovering new therapies.
The global epidemic of obesity and T2D represents one of most pressing, current public health challenges. Traditional therapeutic approaches to treat obesity have largely failed to generate significant reductions in body weight, and more aggressive drug therapies have frequently led to serious adverse effects. Similarly, conventional treatments for T2D have provided little to no improvement in body weight, and insulin has been ascribed to increase it. While bariatric surgery can successfully reduce body weight and dramatically improve glycemic control, for multiple reasons it is not a solution to address the global epidemic. Therefore, non-invasive therapeutic strategies that can combine weight reduction with glycemic control have the potential to address the pathology of T2D and the associated comorbidity of obesity. From the earliest demonstration with lispro-insulin to the most recent discovery of single-molecule, mixed incretin agonists, we have pursued the discovery of chemically optimized macromolecules directed at the successful management of diabetes, obesity, and related diseases. We have coined the term ‘‘chemical biotechnology’’ to reflect the integration of classical small- and large-molecule-based pharmacology while advancing the chemical methodology in synthesis of complex macromolecules. The integrated biology of these unique hormones has provided a library of drug candidates demonstrating enhanced metabolic outcomes across multiple academic and commercial laboratories, with the first examples having advanced to human clinical studies.
582 Cell Metabolism 26, October 3, 2017
Cell Metabolism
Voices Brain Control of Blood Glucose
Bridging the Preclinical Gap
The Making of a Meeting
Lora Heisler
Robert Kruger
Nikla Emambokus
Rowett Institute, University of Aberdeen
Cell Press
Cell Press
There can be little doubt that obesity and T2D represent key global healthcare challenges for the 21st century. To combat these emerging epidemics, new treatment options are a clinical imperative. Substantial progress has been made over the past decade in defining essential hubs within the brain that regulate energy homeostasis. Key hunger and satiety centers and the critical neurochemicals within these regions have been defined with unparalleled precision. A more recent concept is that circuits within the brain may also be harnessed to control blood glucose and insulin sensitivity. The exquisite temporal and spatial precision now afforded by the most recent technology has revealed the existence of essential neurochemicals, receptors, and brain regions with previously undefined glucoregulatory functions. These discoveries highlight the potential of multiple new treatment targets going forward for T2D. One such example with rapid translational potential is the 5-HT2C receptor, given that a 5-HT2C receptor agonist is already in human use for obesity treatment. We have entered an exciting new era in metabolic disease research, rich with the potential to identify multiple new therapeutic targets for disease treatment.
What excites me about the field of metabolic disease therapies is both its urgency, which comes from the dramatic rise in obesity and consequent medical complications, and the field’s extreme interdisciplinary nature. Envisioning a new treatment, or minimizing its side effects, means thinking carefully about the intricate web of metabolic connections within cells, between cells and tissues, and between organ systems. This enforces a kind of holistic thinking that I find inspirational; to me, it is what makes this community so dynamic and productive in both basic and translational research. It has also been particularly apparent in this field that the gulf, once wide, between basic and translational work has dramatically narrowed in recent years. These days my conversations with researchers as often include ongoing or planned clinical trials as they do discussion of new potential targets. This was not the case a decade ago. As a journal, Cell anticipates and wants to foster growth in the number of studies bridging the preclinical gap—containing both new biological insight and clinical trial data. Toward this goal, we hope the symposium will showcase the innovation and increasing precision of metabolic therapies and drive interdisciplinary collaboration in the translational arena.
The idea of a meeting centered around strategies to combat metabolic diseases has been kicking around in the metaphorical hallways of Cell Metabolism for a while now, especially with Anne Granger as a strong advocate for the topic and then again after we launched the Clinical and Translational Report format. However, we were conservatively cautious about whether it was ‘‘the right time’’ to have this conference until a chance conversation with Matthias Tscho¨p, who is a strong advocate for novel therapies, tipped the scale. I surveyed a dozen or so other scientists and my colleague Robert at Cell for their thoughts; the feedback and enthusiasm for a Cell Symposium addressing metabolic disease therapies was unanimous. Together with Angela Messmer-Blust, then our Scientific Editor for Conferences, we put forward the framework proposal for the Cell Symposium, and we were delighted to receive the green light from the Elsevier Conference Department, which has since been instrumental in orchestrating the behind-the-scenes magic that makes a meeting happen. Although there is usually a 2-year lead time for our conferences, we happened to have a slot open for fall 2017 and were fortunate to have Jeffrey Friedman come on board to help us quickly shape a stellar scientific program. The endorsement of all the participants speaks volumes to the urgency of expanding our armamentarium to combat diabetes and other metabolic complications. I, for one, cannot wait to attend this meeting!
Cell Metabolism 26, October 3, 2017 583
Voices Metabolic Disease Therapies In anticipation of our upcoming Cell Symposium on Metabolic Disease Therapies in San Diego, CA, on October 15th–17th (http://cell-symposia.com/metabolic-therapies-2017/), the speakers and organizers share their perspectives on why now, more than ever, cutting-edge research is needed to support effective therapies to combat metabolic disease. Abandoning Conventional Approaches
Surmounting Pitfalls in Translation on the Path to Innovation
Designer Physiology and the Humor in Metabolic Disease
Matthias H. Tscho¨p
Daniel Drucker
Ron Evans
LTRI, Mt. Sinai Hospital
Salk Institute for Biological Studies
Despite a revolution in our understanding of disease pathophysiology, our ability to ameliorate conditions like obesity and NAFLD in the laboratory mouse substantially exceeds our success in translating that knowledge into clinical therapies. Our laboratory, while focused on gut peptides, has been interested in understanding the utility of mouse models as predictors of the therapeutic efficacy of novel metabolic interventions. While mice remain fantastic model organisms for the study of metabolic disease, their suitability as models for chronic metabolic diseases that develop over decades in genetically diverse human subjects has been frequently questioned. More rigor in the replication of studies across species as well as in larger and longer preclinical studies may be a step in the right direction. Enhanced attention to multiple, often profound differences between small laboratory animals and humans with metabolic disease may further sharpen the focus and restrain the rhetoric periodically associated with identification of an important new target, or a ‘‘breakthrough intervention,’’ in a single mouse model studied, often in young mice, over several months. Reassuringly, these caveats are increasingly discussed at scientific meetings, and the level of awareness of translational challenges in the scientific community is slowly but clearly rising. We look forward with enthusiasm to the consideration of new pathways and the development of innovative therapeutic modalities that will make a real difference in arresting the currently rising tsunami of metabolic disease in the years to come.
The study of human physiology dates back to the time of Hippocrates—the Greek physician who developed beliefs on temperament based on earth, water, air, and fire into a medical theory. Each substance had a corresponding humor: black bile, phlegm, blood, and yellow bile, respectively. The underpinning of this brand of Humorism is that endogenous circulating substances act as signals to control bodily function. In the modern era, we can now begin to understand humors, or hormones, as the foundation of physiology: the source of resilience when young and the slouch of frailty as we age. The idea of designer physiology is to use science to manipulate physiology to boost output or function in order to combat the decline associated with aging. Though physiology is inherently adaptive, the generous boundaries of youth become narrowed with age. They become corroded with chronic inflammation, fibrosis, bone loss, weight gain, metabolic disease, Alzheimer’s, and cancer. Knowledge of the molecular architecture of physiologic pathways provides the potential to reactivate a failed or compromised system by rebooting function. The idea of ‘‘resetting’’ physiology has begun with small steps, but its potential is endless. Indeed, the knowledge of any one system is likely to inform us about others. Furthermore, once we understand how to ‘‘game the system,’’ we can begin to generate hybrid or chimeric physiologic pathways and possibly create personalized physiology. What new physiologic function would you like to see invented?
€nchen Helmholtz Zentrum Mu
With their discovery of insulin almost 100 years ago, Frederick Banting and Charles Best turned diabetes from a deadly illness into a chronic disease. Until today, their work has unquestionably represented the most transformative breakthrough within the field of metabolic diseases. While research efforts toward a world without diabetes have steadily increased, both in in number of research efforts and in technical sophistication, so has diabetes incidence and prevalence. Finding a cure rather than incrementally improving manageability of metabolic diseases such as diabetes turns out to be considerably more challenging than expected. Heterogeneity of patient populations and newly uncovered levels of complexity, including epigenetic programming, represent two reasons for the relative lack of novel therapeutics with transformative impact on the pandemic. This Cell Symposium on Metabolic Disease Therapies, therefore, in particular invites scientists to contribute out-of-thebox thinking and discuss unconventional approaches in addition to reporting the latest unpublished advances of existing programs. After 100 years, it may be time to abandon the reliance on conventional approaches and embrace new ideas, even if these are not aligned with established models of metabolic disease pathologies.
Cell Metabolism 26, October 3, 2017 ª 2017 Elsevier Inc. 579
Cell Metabolism
Voices Missing Symbionts?
Inflammometabolism to the Rescue
Mitochondria in Cell Metabolism
Rob Knight
Michael Karin
David Chan
University of California, San Diego
University of California, San Diego
California Institute of Technology
A century ago, complex diseases with effects throughout the body, including the brain, plagued America. The idea that a simple chemical compound could ameliorate a disease as complex as pellagra seemed absurd, and causes were sought in human genetics, food spoilage, and infections. Yet B-complex vitamins in flour, iodine in salt, and vitamin D in milk essentially eliminated these diseases. Today we are faced with dramatic increases in a range of complex chronic diseases—diabetes, Alzheimer’s, asthma, and Parkinson’s are increasing dramatically. What if the underlying causes are as simple as missing nutrients stripped by industrial processing, or missing microbes with which we co-evolved that have been stripped from our bodies by modern antibiotics, delivery and perinatal practices, and separation from the outdoor environment? The prospect of going beyond association studies to truly understand the metabolic effects of our microbial symbionts and the microbiome effects of our metabolites, to truly understand the body at a systems level, excites me tremendously. This is a massive challenge in big data, but advances in technology both to collect the massive datasets and to use increasingly sophisticated computational techniques to extract knowledge from them poise us for a revolution in health in the 21st century as significant as that which occurred in the 20th.
Like all other land-dwelling, multicellular animals, human beings evolved under conditions of periodic and intermittent food supply. Therefore, the ability to store excess calories for a rainy day, or more likely a long period of drought, provides the individual with an obvious evolutionary advantage. Until the so-called ‘‘green revolution,’’ the ability to store excess calories as fat not only under our skin but also within and around our internal organs, especially the liver, was actually beneficial. But nowadays when food is constantly available, excessive lipid storage has become a major health issue. Unfortunately, our understanding of the mechanisms that control lipid biogenesis and metabolism is still sketchy, and such incomplete understanding has hindered therapeutic development. As a result, diseases as common as NAFLD and NASH remain largely untreatable. For many years—and even today—the study of metabolic disease has been in the realm of endocrinology, and endocrinological abnormalities were thought to be the culprit. However, it has become increasingly clear that some of the solutions will come from the fields of inflammation biology and immunology. My own studies and those of others suggest that the immune system, both adaptive and innate, plays a major role in both normal and pathological metabolic regulation. It is my firm belief that the emerging field of immunometabolism will provide us with the new drugs of tomorrow—the blockbusters that will address the medical conditions affecting one-third of humanity.
Considered for decades to be an old science, cell metabolism has again emerged as a timely topic with high relevance to human health and disease. With new technologies enabling a fresh perspective on the biochemicals within cells, there are opportunities to understand how cell metabolism is relevant to diverse biological problems, including aging, stem cell biology, development, and tumorigenesis. As we learn more about these problems, the mitochondrion will undoubtedly constitute a nexus. As the organelles that generate the bulk of cellular ATP through oxidative phosphorylation, mitochondria are clearly central to metabolism. However, oxidative phosphorylation is just the tip of the iceberg—through their functions in intermediary metabolism, apoptosis, calcium handling, iron-sulfur biosynthesis, heme synthesis, and innate immunity, mitochondria impact a surprisingly wide range of cell biology. As with metabolism, the study of mitochondria has undergone a remarkable renaissance, and our appreciation for the complexity and breadth of their cellular functions continues to grow. Mitochondria are no longer the traditional organelles depicted in classical textbooks; they are dynamic organelles whose shape, localization, turnover, and interactions with other organelles change depending on the cellular environment. They are important in all cells, but play particularly important roles in neurons and muscles. As our ideas of metabolism and mitochondria evolve, the challenge will be to devise new therapies to modulate their impact on human diseases.
580 Cell Metabolism 26, October 3, 2017
Cell Metabolism
Voices To Target Mitochondrial Dynamics
Body-Brain Communication
Ground Rules for Behavior
Sabrina Diano
Garret Stuber
Scott Sternson
Yale University School of Medicine
University of North Carolina at Chapel Hill
Janelia Research Campus, HHMI
Almost 20 years ago, we identified mitochondria as a dynamically changing organelle system in hypothalamic neuronal populations that are responsible for feeding and glucose control. We and others went on to show that mitochondrial plasticity and dynamics in neuronal populations are not merely passive responses to the changing functionality of these cells, but actually play crucial roles in enabling proper neuronal responses to changing peripheral cues. Thus, it is highly plausible not only that dynamically changing mitochondrial structure and related function may be relevant for physiological adaptation of brain cells but also that impairment in these processes might be key in the development of metabolic pathologies such as type 2 diabetes (T2D) and other obesity-associated impairments. Thus, targeting emerging molecular drivers of mitochondrial dynamics opens a novel avenue to develop therapeutics to treat metabolic diseases. However, there are both methodological and conceptual roadblocks that need to be conquered in order to make significant advances in these new directions. For example, change in mitochondrial structure and function may vary between different cell and tissue types. It is therefore unlikely that a single approach affecting mitochondrial function in a given direction will benefit the whole organism. In addition, experimental tools to monitor and analyze dynamically changing mitochondrial functions in real time are limited and do not offer analyses of subpopulations of neurons in different parts of the brain. Thus, to target mitochondrial dynamics for therapeutic development of metabolic disorders, these obstacles must be forcefully and directly addressed.
Optimal control of feeding and metabolism requires the brain and other tissues in the body to be in constant communication with each other. Satiety-signaling hormones as well as other factors released from the periphery impact brain function not only to regulate feeding but also to contribute to an individual’s general well-being. Despite a general agreement within the field that hormones and other peripheral signals impact the nervous system to promote appropriate behavioral output, such as food seeking when hungry, the way in which peripheral signals associated with feeding and body weight impact molecularly defined cell types and circuits in the brain remains largely unexplored. In order to continue to push the field forward, we must work to better define, mechanistically, how cells and circuits within the brain are modified by peripheral signals. Additionally, while it is experimentally convenient to study how single hormones impact brain function, metabolic disease is multifaceted: it affects multiple organ systems. Thus, determining how multifactorial changes in hormonal composition may synergistically impact brain function could provide better insight into how metabolic disease impacts the nervous system. By leveraging recent technological advances in mass spectroscopy, single-cell transcriptional profiling, and large-scale calcium imaging of neural network activity, it may soon become possible to identify and prioritize the most promising aspects of body-brain communication to target for next-generation treatments for metabolic diseases.
Brain stimulation control of appetite stands out as one of the most dramatic behavioral responses in neuroscience. I made the leap from synthetic chemistry to the neurobiology of appetite because I became interested in the ‘‘ground rules’’ for motivated behavior. The fact that a localized neuronal activation can elicit complex, goal-direct, motivated behavior provides an entry point to uncovering the clever tricks natural selection employs to ensure that an organism reliably satisfies its needs in an unpredictable world. The answer lies in understanding how complex motivated behaviors associated with survival are embedded in specialized neural circuits. Many challenges have impeded progress in this interesting area: deep and intermingled brain circuits, challenges with quantitatively monitoring physiologic state, and the complexity of behaviors such as food-seeking and consumption. However, improvements in the techniques of deep-brain neuroscience and molecularly defined neural circuitry are putting within reach an understanding of appetite that stretches across all of the length scales of biology, from molecules to neurons, circuits, and behavior. I am confident that our understanding will increase at least 10-fold in the next 10 years. Hopefully, the rapid growth of knowledge about the brain’s control over appetite and metabolism will enable a systematic process to develop safe and effective human therapies for overeating and obesity.
Cell Metabolism 26, October 3, 2017 581
Cell Metabolism
Voices From Genes to Biology
Metabolites and Metabolic Disease
Chemical Evolution of Hormones
Ruth Loos
Barbara B. Kahn, MD
Richard DiMarchi
Icahn School of Medicine at Mount Sinai
Beth Israel Deaconess & Harvard Medical School
Chemistry, Indiana University
Obesity is a complex, multifactorial, and heritable disease. Yet the importance of a genetic contribution is often dismissed, as—many will declare—the obesity epidemic is the consequence of changes in people’s diet and physical activity levels, not in their genome. This is only partially true, however, as it is those who are the most genetically susceptible who gain the most weight in this changing environment. Insight in the genetics of obesity means insight in its underlying biology. Over the past decade, genome-wide screens for obesity have identified hundreds of genetic loci that point to the brain as a key organ in the control of body weight regulation, consistent with observations from monogenic cases of extreme and early onset obesity. A major challenge in the field is translation of these loci into ‘‘tangible’’ genes that can be studied in more experimental settings to get to the bottom of their biology. We try to close the gap between gene discovery and functional follow-up by focusing on more refined phenotypes, such as body fat percentage, specific adipose depots, and biomarkers, and on variants with a high potential to disrupt gene function. It is only once causal genes are identified that we can start thinking about therapeutics, and this requires geneticists and physiologists to work together even more than before.
Reports at the 2002 International Congress on Obesity predicted that this is the first generation in which children will die before their parents. This results from the lifelong burden of obesity, insulin resistance, and T2D emerging in the pediatric population. While recent advances in T2D treatment are substantial, T2D prevalence continues to increase, and many diabetic people are still inadequately treated. To improve outcomes, we need safe insulin-sensitizing medications. Recent technological advances have enabled measurements of thousands of metabolites in biologic samples. ‘‘Signatures’’ of amino acids, fatty acids, and bile acids are being identified in association with obesity and T2D. Interpreting metabolite information presents challenges unlike those encountered with the expansion of genomic data. It is not obvious which metabolite signatures are causes of the metabolic aberrations and which are consequences. What initiates the process, and in which tissues does it start? The roles of dietary nutrients, alterations in pathways that metabolize these nutrients, and gut microbiota need to be determined. We need to understand the mechanisms by which metabolites act as signaling molecules and the functional consequences of metabolite and lipid modification of proteins and cell membrane dynamics. The sheer number of these metabolites, the interconnectedness of their metabolic pathways, and their ability to alter intertissue communication makes this a compelling frontier for understanding metabolic disease and discovering new therapies.
The global epidemic of obesity and T2D represents one of most pressing, current public health challenges. Traditional therapeutic approaches to treat obesity have largely failed to generate significant reductions in body weight, and more aggressive drug therapies have frequently led to serious adverse effects. Similarly, conventional treatments for T2D have provided little to no improvement in body weight, and insulin has been ascribed to increase it. While bariatric surgery can successfully reduce body weight and dramatically improve glycemic control, for multiple reasons it is not a solution to address the global epidemic. Therefore, non-invasive therapeutic strategies that can combine weight reduction with glycemic control have the potential to address the pathology of T2D and the associated comorbidity of obesity. From the earliest demonstration with lispro-insulin to the most recent discovery of single-molecule, mixed incretin agonists, we have pursued the discovery of chemically optimized macromolecules directed at the successful management of diabetes, obesity, and related diseases. We have coined the term ‘‘chemical biotechnology’’ to reflect the integration of classical small- and large-molecule-based pharmacology while advancing the chemical methodology in synthesis of complex macromolecules. The integrated biology of these unique hormones has provided a library of drug candidates demonstrating enhanced metabolic outcomes across multiple academic and commercial laboratories, with the first examples having advanced to human clinical studies.
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Cell Metabolism
Voices Brain Control of Blood Glucose
Bridging the Preclinical Gap
The Making of a Meeting
Lora Heisler
Robert Kruger
Nikla Emambokus
Rowett Institute, University of Aberdeen
Cell Press
Cell Press
There can be little doubt that obesity and T2D represent key global healthcare challenges for the 21st century. To combat these emerging epidemics, new treatment options are a clinical imperative. Substantial progress has been made over the past decade in defining essential hubs within the brain that regulate energy homeostasis. Key hunger and satiety centers and the critical neurochemicals within these regions have been defined with unparalleled precision. A more recent concept is that circuits within the brain may also be harnessed to control blood glucose and insulin sensitivity. The exquisite temporal and spatial precision now afforded by the most recent technology has revealed the existence of essential neurochemicals, receptors, and brain regions with previously undefined glucoregulatory functions. These discoveries highlight the potential of multiple new treatment targets going forward for T2D. One such example with rapid translational potential is the 5-HT2C receptor, given that a 5-HT2C receptor agonist is already in human use for obesity treatment. We have entered an exciting new era in metabolic disease research, rich with the potential to identify multiple new therapeutic targets for disease treatment.
What excites me about the field of metabolic disease therapies is both its urgency, which comes from the dramatic rise in obesity and consequent medical complications, and the field’s extreme interdisciplinary nature. Envisioning a new treatment, or minimizing its side effects, means thinking carefully about the intricate web of metabolic connections within cells, between cells and tissues, and between organ systems. This enforces a kind of holistic thinking that I find inspirational; to me, it is what makes this community so dynamic and productive in both basic and translational research. It has also been particularly apparent in this field that the gulf, once wide, between basic and translational work has dramatically narrowed in recent years. These days my conversations with researchers as often include ongoing or planned clinical trials as they do discussion of new potential targets. This was not the case a decade ago. As a journal, Cell anticipates and wants to foster growth in the number of studies bridging the preclinical gap—containing both new biological insight and clinical trial data. Toward this goal, we hope the symposium will showcase the innovation and increasing precision of metabolic therapies and drive interdisciplinary collaboration in the translational arena.
The idea of a meeting centered around strategies to combat metabolic diseases has been kicking around in the metaphorical hallways of Cell Metabolism for a while now, especially with Anne Granger as a strong advocate for the topic and then again after we launched the Clinical and Translational Report format. However, we were conservatively cautious about whether it was ‘‘the right time’’ to have this conference until a chance conversation with Matthias Tscho¨p, who is a strong advocate for novel therapies, tipped the scale. I surveyed a dozen or so other scientists and my colleague Robert at Cell for their thoughts; the feedback and enthusiasm for a Cell Symposium addressing metabolic disease therapies was unanimous. Together with Angela Messmer-Blust, then our Scientific Editor for Conferences, we put forward the framework proposal for the Cell Symposium, and we were delighted to receive the green light from the Elsevier Conference Department, which has since been instrumental in orchestrating the behind-the-scenes magic that makes a meeting happen. Although there is usually a 2-year lead time for our conferences, we happened to have a slot open for fall 2017 and were fortunate to have Jeffrey Friedman come on board to help us quickly shape a stellar scientific program. The endorsement of all the participants speaks volumes to the urgency of expanding our armamentarium to combat diabetes and other metabolic complications. I, for one, cannot wait to attend this meeting!
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