E D I T O R I A L
Editorial: Molecular Obesity Research: Lessons Learned? Rexford S. Ahima Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, and the Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
his editorial is a tribute to Douglas Coleman, PhD, a giant in the field of obesity research, who died on April 16, 2014. In the 1970s, Coleman conducted elegant studies at The Jackson Laboratory in Bar Harbor, Maine, which led him to propose the existence of a circulating factor linked to the pathogenesis of obesity (1, 2). His seminal cross-circulation (parabiosis) experiments in genetically obese mice formed the basis of the current view of adipose tissue as an endocrine organ linked to regulation of feeding and body weight.
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Global Obesity Crisis Globally, more than 1.4 billion adults older than age 20 years and 40 million children younger than age 5 years are overweight (3). Overweight and obesity are characterized by excessive fat accumulation. The body mass index (BMI), defined as a person’s weight in kilograms divided by the square of the height in meters, is often used as a measure of fatness. The World Health Organization defines overweight in adults as a BMI ⱖ25 and obesity as a BMI ⱖ30. The prevalence of obesity has more than doubled in most parts of the world since 1980 (4). In 2008, 35% of adults worldwide were overweight and 11% were obese (3). Among these, ⬎200 million men and nearly 300 million women were obese. More than one third of US adults (34.9%) are obese (5). Non-Hispanic blacks have the highest age-adjusted rates of obesity (47.8%), followed by Hispanics (42.5%), non-Hispanic whites (32.6%), and non-Hispanic Asians (10.8%) (5). Obesity is also higher among middle-aged adults, aged 40 to 59 years old (39.5%), than among younger adults, aged 20 to 39 (30.3%), or adults 60 years or older (35.4%) (5). ISSN Print 0888-8809 ISSN Online 1944-9917 Printed in U.S.A. Copyright © 2014 by the Endocrine Society
doi: 10.1210/me.2014-1140
The fundamental cause of overweight and obesity is an imbalance between energy intake and expenditure. Although genetic factors undoubtedly influence the pathogenesis of obesity, the rise in obesity is mainly attributed to increased intake of foods rich in fat and sugar, and a decrease in physical activity due to rapid urbanization, changes in modes of transportation, agriculture, food processing, distribution, marketing, and other aspects of modern societies that promote a sedentary lifestyle. Overweight and obesity are the fifth leading risk for global deaths. It is estimated that 2.8 million adults die worldwide each year as a result of being overweight or obese (3). In addition, 44% of the diabetes burden, 23% of the ischemic heart disease burden, and between 7% and 41% of cancer burdens are attributable to overweight and obesity (3). Obesity is also a risk factor for obstructive sleep apnea, nonalcoholic fatty liver disease, osteoarthritis, infertility, and several other ailments. Obesity has enormous economic costs. In 2008, it was estimated that the annual medical cost of obesity in the United States was $147 billion, and the medical costs for people who were obese were $1429 higher than those of normal weight (5). The overall economic burden of obesity, including disability, low productivity, provision of social services, and premature deaths may be as high as 3 times the medical cost. Many developing countries now face a double burden of infectious diseases and undernutrition and an upsurge in obesity and other noncommunicable disease risk factors. Children in developing countries are vulnerable to undernutrition and are also exposed to malnutrition from high-fat and high-sugar and foods, low in micronutrients, which tend to be cheaper but have very poor nutritional quality. The “nutritional transition” trend has resulted in Abbreviations: BMI, body mass index; db, diabetes; ob, obese; VHN, ventromedial hypothalamic nucleus; WT, wild-type.
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marked increases in childhood obesity in developing countries and poses major health and socioeconomic threats worldwide. Indeed, 65% of the world’s population live in countries where overweight and obesity account for more deaths than underweight (3). These gloomy statistics have spurred governments and organizations to develop preventive strategies focused on education of individuals and communities to make healthier choice of foods, promotion of affordable and accessible healthy foods to all especially the poorest individuals, and changes in the physical infrastructure and workplace to limit sedentary lifestyle. Importantly, the obesity epidemic has also stimulated research efforts to understand biological mechanisms and to improve and develop novel medical and surgical therapies.
Obesity Pathogenesis: From Hypothalamic Lesions to Leptin This year marks the 20th anniversary of the discovery of leptin, a hormone that plays a critical role in the regulation of appetite and body weight (6). Evidence for the existence of physiologic mechanisms of body weight regulation dates back to classic studies several decades ago (7). Based on lesion experiments of rat hypothalamus, it was postulated that a “satiety center” existed in the medial hypothalamus, whereas a “feeding center” existed in the lateral hypothalamus. Destruction of the ventromedial hypothalamic nucleus (VMH) led to voracious feeding and massive weight gain, whereas destruction of the lateral hypothalamus led to starvation and weight loss. When obese VMH-lesioned rats were surgically joined (parabiosis) with normal rats through their subcutaneous tissues, allowing a slow exchange of blood-borne factors, the normal rats ate less food and lost weight. Therefore, it was postulated that the obese VMH-lesioned rats failed to respond to a peripheral factor that inhibits feeding, and that they overproduced a factor that crossed into the circulation of the normal rats to suppress feeding and reduce body weight. This earlier hypothesis based on a simple but elegant paradigm was proven correct after the discovery of genetically obese mice at The Jackson Laboratory. In the 1950s, an autosomal recessive obese mouse exhibiting hyperphagia, rapid onset obesity, and a variety of endocrine abnormalities was identified, and a mutation designated obese (ob) was mapped to chromosome 6 (8). Later, a second obese mouse with features very similar to those of ob/ob mice was identified, and this mutation mapped to chromosome 4 and was designated diabetes (db) because the mice had high blood glucose on a C57BLKS
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genetic background (9). Coleman used these mouse models to probe the molecular basis of obesity. When the normal (wild-type [WT]) or db/db mice were parabiosed with ob/ob mice, the latter developed a severe reduction in food intake and weight loss (1, 2) (Figure 1). In contrast, the WT mice were unaffected when they were parabiosed with ob/ob mice, but stopped eating and lost substantial weight when they were parabiosed with db/db mice (Figure 1). These results led Coleman to surmise that the ob/ob mice lacked a blood-borne satiety factor produced by WT and db/db mice. The db/db mice were insensitive to the satiety factor because they lacked the receptor. These results were met with skepticism for many years because no specific satiety factor or site of action was identified. Two decades later, Friedman and colleagues transformed the field of metabolism by cloning the ob gene (6). In a landmark article in 1994, they described the ob gene as a 4.5-kb transcript expressed exclusively in adipose tissue, which encoded a secreted peptide with 167 amino acids (6). Treatment of ob/ob mice with OB protein reversed overeating and obesity; hence, the OB protein was named “leptin” from the Greek root leptos meaning “thin” (10 –12). Leptin was more potent when injected directly into the brain rather than peripherally. The db/db mice did not respond to leptin in accordance with Coleman’s hypothesis that db/db mice lack a sensing mechanism of the blood-borne satiety factor. Subsequent research led to the discovery that the db locus encodes leptin receptors that are alternatively spliced members of the
Figure 1. Parabiosis experiments in mice. Seminal studies by Coleman showed that parabiosis (cross-circulation) of ob/ob and normal WT mice resulted in weight loss in ob/ob mice. In contrast, parabiosis of db/db and WT resulted in weight loss in WT. Parabiosis of db/db and ob/ob mice resulted in weight loss in ob/ob mice. It was therefore postulated that the ob locus produces a circulating factor that inhibits food intake, and the db locus encodes the receptor for the circulating satiety factor.
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cytokine receptor family (13, 14). The db allele, unlike the other variants, was highly expressed in the hypothalamus and predicted to mediate Jak/Stat signaling (15). This was confirmed in studies showing that leptin activates STAT3 in the hypothalamus when administered peripherally and that deletion of this long leptin receptor variant in neurons resulted in overeating and obesity (16). Coleman and Friedman were awarded the prestigious Lasker Award for basic medical research in 2010, for their seminal contributions to obesity research. The discovery of leptin provided powerful molecular tools for studying neural circuits that control energy balance (16, 17). Leptin is transported into the brain and acts in the hypothalamus to regulate feeding, energy expenditure, the neuroendocrine axis, and metabolism (Figure 2). The net effect of leptin is to inhibit food intake and decrease body weight. Leptin also controls the hedonic aspects of food intake and interacts with signals from the gut, brainstem, and other brain regions (16, 17). The discovery of leptin has stimulated research efforts to understand the roles of other adipose-derived hormones (adipokines), neuropeptides involved in the regulation of feeding and metabolism, the interaction of genetic and environmental factors in obesity, and therapeutic targets of obesity and related diseases. As in mice, congenital leptin deficiency or defective leptin receptors cause overeating and rapid onset of obesity in humans (18, 19). Treatment with recombinant leptin causes dramatic weight loss in patients harboring rare
Figure 2. Hypothalamic neuronal targets of leptin. Leptin inhibits feeding and increases energy expenditure by directly suppressing neuropeptide Y (NPY) and increasing proopiomelanocortin (POMC). Neurons in the arcuate nucleus expressing these peptides project to the paraventricular nucleus and lateral hypothalamic area, resulting in increases in CRH and TRH and reductions in melanin-concentrating hormone (MCH) and orexins. The net effect of leptin is to suppress appetite, reduce weight, and enhance fatty acid oxidation and insulin sensitivity in peripheral organs. AGRP, Agouti-related peptide; LRb, long leptin receptor; MC4R, melanocortin 4 receptor; MSH, melaninstimulating hormone; TG, triglycerides.
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loss-of-function mutations in the LEP gene (23, 24). However, common forms of obesity due to overnutrition and lack of exercise lead to elevated leptin levels and poor response to leptin treatment, suggesting leptin resistance (20, 25). Mediators of leptin resistance, eg, suppressor of cytokine signaling 3 (SOC3) and tyrosine phosphatase PTP1b, have been linked to diet-induced obesity in mice (16, 17), but whether these molecules are dysregulated in common forms of human obesity is unknown.
Lessons Learned? Although leptin was named for its antiobesity effect in mice, evidence suggests that a major physiologic role of leptin is to signal energy deficiency to the brain and elicit hormonal, metabolic, and behavioral responses to restore energy stores (21, 22). Leptin levels fall rapidly during fasting and mediate the suppression of reproduction, thyroid hormone, and immune function (21). These defects are also seen in ob/ob mice with total leptin deficiency. Partial leptin deficiency leads to hypogonadism in starvation, hypothalamic amenorrhea, and lipodystrophy in humans (26). Thus, leptin has a broad dose-response range in mediating the response to starvation as leptin levels fall, as well as limiting overfeeding as the levels rise (20, 22). It is possible that leptin resistance confers an evolutionary advantage by promoting energy storage against the threat of starvation. Leptin has myriad effects on glucose and lipid metabolism, brain development, hematopoiesis, inflammation, bone biology, cellular growth and differentiation, and other biological systems, apart from energy homeostasis (7, 16). This happens often in endocrinology when a hormone is named initially for a presumed function and is found later to exert multiple effects. As an example, insulin has a major role in regulating glucose levels, but this is not the only function of insulin under normal or pathologic conditions. Insulin has diverse effects on lipid and protein metabolism, cell growth and differentiation, and other systems. Obesity is a highly complex disorder of energy metabolism that culminates in excessive fat accumulation in adipose, liver, skeletal muscle, and other organs. Obesity is influenced by genetic and environmental factors, particularly diet and exercise. Therefore, animal and cellular studies into obesity pathogenesis and drug discovery need to consider interactions of complex processes instead of simple linear pathways. The role of genetics in human obesity was recognized in twin studies many decades ago (27). The discovery of mutations associated with human obesity has illuminated our knowledge (28). Genetic loci
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identified in genome-wide association studies have been linked with obesity; however, the overall trait variance explained by these associated loci is very small, suggesting that most of the familial aggregation of obesity may be influenced by environmental modulation of epigenetic processes. The impact of intrauterine and postnatal environmental factors on the programming of metabolism is an exciting area for exploration. Another area that needs improvement is the assessment of body composition. Our current definition of obesity based on a threshold BMI value ignores population distribution patterns of weight and fat. The BMI is not a precise measure of fat, does not account for lean mass and fat location, and does not consider racial/ethnic and sex differences in fat content and distribution. Visceral fat and muscle mass are better predictors of insulin resistance, diabetes, and other metabolic disorders. Therefore, there is an urgent need for accurate and affordable methods for evaluating body composition in clinical and population studies (29). Our knowledge of the mechanisms linking obesity to the development of diabetes, cardiovascular disease, cancer, and other obesity-related diseases is rudimentary. It is well known that obesity is associated with insulin resistance and activation of innate immunity, but are they causally linked with a range of obesity-related diseases, such as diabetes, cancer, infertility, and osteoarthritis (30)? Can we harness information on adipokines, cytokines, and other biomarkers for diagnostic purposes in obesity or for the development of specific drugs for diseases associated with obesity? Despite the enormous progress in understanding of molecular mechanisms relating to weight loss, current dietary and medical interventions often fail to sustain long-term weight loss (31). Gastric bypass surgery, which is the most effective treatment of morbid obesity, rapidly reverses diabetes in the absence of substantial weight loss (32). These findings demand a rethinking of the treatment of obesity and related diseases. We need novel prevention and treatment strategies based on a better understanding of the biochemistry of macronutrients and micronutrients, energy metabolism, impact of lifestyle and environmental factors on homeostatic mechanisms, potential roles of endocrine disruptors and gut microbiota on metabolism, and multiple pathways linking genetics and the environment. Regardless of these vexing issues, it is safe to say that we have made tremendous strides in understanding metabolism and obesity. There is a broad of range of exciting research opportunities spanning cellular models, genetically modified animal models, patients with various genetic defects, and population studies. Molecular tools and
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techniques are essential for unraveling the mysteries of energy metabolism, obesity, and disease pathogenesis. Molecular Endocrinology will continue to play a crucial role by providing the basic and translational research communities ample opportunities to disseminate their work. Rexford S. Ahima, MD, PhD Editor, Molecular Endocrinology
Acknowledgments Address all correspondence and requests for reprints to: Rexford S. Ahima, MD, PhD, University of Pennsylvania, Perelman School of Medicine, 12–104 Smilow Center for Translational Research, 3400 Civic Center, Building 421, Philadelphia, PA 19104. E-mail: [email protected]. This work was supported by the National Institute of Health (Grant P01-DK049210; P30-DK19525). Disclosure Summary: The author has nothing to disclose.
References 1. Coleman DL, Hummel KP. Effects of parabiosis of normal with genetically diabetic mice. Am J Physiol. 1969;217:1298 –1304. 2. Coleman DL. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia. 1973;9:294 –298. 3. Obesity and overweight. Fact sheet no. 311, 2013. World Health Organization website. http://www.who.int/mediacentre/factsheets/ fs311/en/. Accessed April 29, 2014. 4. Ahima RS. Digging deeper into obesity. J Clin Invest. 2011;121: 2076 –2079. 5. Adult obesity facts. Centers for Disease Control and Prevention website. http://www.cdc.gov/obesity/data/adult.html. Accessed April 29, 2014. 6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425– 432. 7. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21:263– 307. 8. Ingalls AM, Dickei MM, Snell GD. Obese, a new mutation in the house mouse. J Hered. 1950;41:317–318. 9. Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science. 1966;153:1127–1128. 10. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269: 543–546. 11. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546 –549. 12. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540 –543. 13. Tartaglia LA, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–1271. 14. Chua SC Jr, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science. 1996;271:994 –996. 15. Baumann H, et al. The full-length leptin receptor has signaling
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16. 17. 18.
19.
20. 21. 22.
23. 24.
capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci USA. 1996;93:8374 – 8378. Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70:537–556. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest. 2011;121:2087–2093. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–908. Clément K, Vaisse C, Lahlou N. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398 – 401. Flier JS. Clinical review 94: What’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab. 1998;83:1407–1413. Ahima RS, Prabakaran D, Mantzoros C. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250 –252. Ahima RS, Kelly J, Elmquist JK, Flier JS. Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia. Endocrinology. 1999;140:4923– 4931. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570 –578. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/meta-
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25.
26.
27.
28. 29. 30.
31. 32.
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bolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110:1093–1103. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282:1568 –1575. Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA, Mantzoros CS. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab. 2013;18:29 – 42. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The bodymass index of twins who have been reared apart. N Engl J Med. 1990;322:1483–1487. Ramachandrappa S, Farooqi IS. Genetic approaches to understanding human obesity. J Clin Invest. 2011;121:2080 –2086. Ahima RS, Lazar MA. Physiology. The health risk of obesity– better metrics imperative. Science. 2013;341:856 – 858. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18: 363–374. Bray GA, Ryan DH. Update on obesity pharmacotherapy. Ann NY Acad Sci. 2014;1311:1–13. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol. 2013;10:575– 584.
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Editorial: Molecular Obesity Research: Lessons Learned? Rexford S. Ahima Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, and the Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
his editorial is a tribute to Douglas Coleman, PhD, a giant in the field of obesity research, who died on April 16, 2014. In the 1970s, Coleman conducted elegant studies at The Jackson Laboratory in Bar Harbor, Maine, which led him to propose the existence of a circulating factor linked to the pathogenesis of obesity (1, 2). His seminal cross-circulation (parabiosis) experiments in genetically obese mice formed the basis of the current view of adipose tissue as an endocrine organ linked to regulation of feeding and body weight.
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Global Obesity Crisis Globally, more than 1.4 billion adults older than age 20 years and 40 million children younger than age 5 years are overweight (3). Overweight and obesity are characterized by excessive fat accumulation. The body mass index (BMI), defined as a person’s weight in kilograms divided by the square of the height in meters, is often used as a measure of fatness. The World Health Organization defines overweight in adults as a BMI ⱖ25 and obesity as a BMI ⱖ30. The prevalence of obesity has more than doubled in most parts of the world since 1980 (4). In 2008, 35% of adults worldwide were overweight and 11% were obese (3). Among these, ⬎200 million men and nearly 300 million women were obese. More than one third of US adults (34.9%) are obese (5). Non-Hispanic blacks have the highest age-adjusted rates of obesity (47.8%), followed by Hispanics (42.5%), non-Hispanic whites (32.6%), and non-Hispanic Asians (10.8%) (5). Obesity is also higher among middle-aged adults, aged 40 to 59 years old (39.5%), than among younger adults, aged 20 to 39 (30.3%), or adults 60 years or older (35.4%) (5). ISSN Print 0888-8809 ISSN Online 1944-9917 Printed in U.S.A. Copyright © 2014 by the Endocrine Society
doi: 10.1210/me.2014-1140
The fundamental cause of overweight and obesity is an imbalance between energy intake and expenditure. Although genetic factors undoubtedly influence the pathogenesis of obesity, the rise in obesity is mainly attributed to increased intake of foods rich in fat and sugar, and a decrease in physical activity due to rapid urbanization, changes in modes of transportation, agriculture, food processing, distribution, marketing, and other aspects of modern societies that promote a sedentary lifestyle. Overweight and obesity are the fifth leading risk for global deaths. It is estimated that 2.8 million adults die worldwide each year as a result of being overweight or obese (3). In addition, 44% of the diabetes burden, 23% of the ischemic heart disease burden, and between 7% and 41% of cancer burdens are attributable to overweight and obesity (3). Obesity is also a risk factor for obstructive sleep apnea, nonalcoholic fatty liver disease, osteoarthritis, infertility, and several other ailments. Obesity has enormous economic costs. In 2008, it was estimated that the annual medical cost of obesity in the United States was $147 billion, and the medical costs for people who were obese were $1429 higher than those of normal weight (5). The overall economic burden of obesity, including disability, low productivity, provision of social services, and premature deaths may be as high as 3 times the medical cost. Many developing countries now face a double burden of infectious diseases and undernutrition and an upsurge in obesity and other noncommunicable disease risk factors. Children in developing countries are vulnerable to undernutrition and are also exposed to malnutrition from high-fat and high-sugar and foods, low in micronutrients, which tend to be cheaper but have very poor nutritional quality. The “nutritional transition” trend has resulted in Abbreviations: BMI, body mass index; db, diabetes; ob, obese; VHN, ventromedial hypothalamic nucleus; WT, wild-type.
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marked increases in childhood obesity in developing countries and poses major health and socioeconomic threats worldwide. Indeed, 65% of the world’s population live in countries where overweight and obesity account for more deaths than underweight (3). These gloomy statistics have spurred governments and organizations to develop preventive strategies focused on education of individuals and communities to make healthier choice of foods, promotion of affordable and accessible healthy foods to all especially the poorest individuals, and changes in the physical infrastructure and workplace to limit sedentary lifestyle. Importantly, the obesity epidemic has also stimulated research efforts to understand biological mechanisms and to improve and develop novel medical and surgical therapies.
Obesity Pathogenesis: From Hypothalamic Lesions to Leptin This year marks the 20th anniversary of the discovery of leptin, a hormone that plays a critical role in the regulation of appetite and body weight (6). Evidence for the existence of physiologic mechanisms of body weight regulation dates back to classic studies several decades ago (7). Based on lesion experiments of rat hypothalamus, it was postulated that a “satiety center” existed in the medial hypothalamus, whereas a “feeding center” existed in the lateral hypothalamus. Destruction of the ventromedial hypothalamic nucleus (VMH) led to voracious feeding and massive weight gain, whereas destruction of the lateral hypothalamus led to starvation and weight loss. When obese VMH-lesioned rats were surgically joined (parabiosis) with normal rats through their subcutaneous tissues, allowing a slow exchange of blood-borne factors, the normal rats ate less food and lost weight. Therefore, it was postulated that the obese VMH-lesioned rats failed to respond to a peripheral factor that inhibits feeding, and that they overproduced a factor that crossed into the circulation of the normal rats to suppress feeding and reduce body weight. This earlier hypothesis based on a simple but elegant paradigm was proven correct after the discovery of genetically obese mice at The Jackson Laboratory. In the 1950s, an autosomal recessive obese mouse exhibiting hyperphagia, rapid onset obesity, and a variety of endocrine abnormalities was identified, and a mutation designated obese (ob) was mapped to chromosome 6 (8). Later, a second obese mouse with features very similar to those of ob/ob mice was identified, and this mutation mapped to chromosome 4 and was designated diabetes (db) because the mice had high blood glucose on a C57BLKS
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genetic background (9). Coleman used these mouse models to probe the molecular basis of obesity. When the normal (wild-type [WT]) or db/db mice were parabiosed with ob/ob mice, the latter developed a severe reduction in food intake and weight loss (1, 2) (Figure 1). In contrast, the WT mice were unaffected when they were parabiosed with ob/ob mice, but stopped eating and lost substantial weight when they were parabiosed with db/db mice (Figure 1). These results led Coleman to surmise that the ob/ob mice lacked a blood-borne satiety factor produced by WT and db/db mice. The db/db mice were insensitive to the satiety factor because they lacked the receptor. These results were met with skepticism for many years because no specific satiety factor or site of action was identified. Two decades later, Friedman and colleagues transformed the field of metabolism by cloning the ob gene (6). In a landmark article in 1994, they described the ob gene as a 4.5-kb transcript expressed exclusively in adipose tissue, which encoded a secreted peptide with 167 amino acids (6). Treatment of ob/ob mice with OB protein reversed overeating and obesity; hence, the OB protein was named “leptin” from the Greek root leptos meaning “thin” (10 –12). Leptin was more potent when injected directly into the brain rather than peripherally. The db/db mice did not respond to leptin in accordance with Coleman’s hypothesis that db/db mice lack a sensing mechanism of the blood-borne satiety factor. Subsequent research led to the discovery that the db locus encodes leptin receptors that are alternatively spliced members of the
Figure 1. Parabiosis experiments in mice. Seminal studies by Coleman showed that parabiosis (cross-circulation) of ob/ob and normal WT mice resulted in weight loss in ob/ob mice. In contrast, parabiosis of db/db and WT resulted in weight loss in WT. Parabiosis of db/db and ob/ob mice resulted in weight loss in ob/ob mice. It was therefore postulated that the ob locus produces a circulating factor that inhibits food intake, and the db locus encodes the receptor for the circulating satiety factor.
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cytokine receptor family (13, 14). The db allele, unlike the other variants, was highly expressed in the hypothalamus and predicted to mediate Jak/Stat signaling (15). This was confirmed in studies showing that leptin activates STAT3 in the hypothalamus when administered peripherally and that deletion of this long leptin receptor variant in neurons resulted in overeating and obesity (16). Coleman and Friedman were awarded the prestigious Lasker Award for basic medical research in 2010, for their seminal contributions to obesity research. The discovery of leptin provided powerful molecular tools for studying neural circuits that control energy balance (16, 17). Leptin is transported into the brain and acts in the hypothalamus to regulate feeding, energy expenditure, the neuroendocrine axis, and metabolism (Figure 2). The net effect of leptin is to inhibit food intake and decrease body weight. Leptin also controls the hedonic aspects of food intake and interacts with signals from the gut, brainstem, and other brain regions (16, 17). The discovery of leptin has stimulated research efforts to understand the roles of other adipose-derived hormones (adipokines), neuropeptides involved in the regulation of feeding and metabolism, the interaction of genetic and environmental factors in obesity, and therapeutic targets of obesity and related diseases. As in mice, congenital leptin deficiency or defective leptin receptors cause overeating and rapid onset of obesity in humans (18, 19). Treatment with recombinant leptin causes dramatic weight loss in patients harboring rare
Figure 2. Hypothalamic neuronal targets of leptin. Leptin inhibits feeding and increases energy expenditure by directly suppressing neuropeptide Y (NPY) and increasing proopiomelanocortin (POMC). Neurons in the arcuate nucleus expressing these peptides project to the paraventricular nucleus and lateral hypothalamic area, resulting in increases in CRH and TRH and reductions in melanin-concentrating hormone (MCH) and orexins. The net effect of leptin is to suppress appetite, reduce weight, and enhance fatty acid oxidation and insulin sensitivity in peripheral organs. AGRP, Agouti-related peptide; LRb, long leptin receptor; MC4R, melanocortin 4 receptor; MSH, melaninstimulating hormone; TG, triglycerides.
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loss-of-function mutations in the LEP gene (23, 24). However, common forms of obesity due to overnutrition and lack of exercise lead to elevated leptin levels and poor response to leptin treatment, suggesting leptin resistance (20, 25). Mediators of leptin resistance, eg, suppressor of cytokine signaling 3 (SOC3) and tyrosine phosphatase PTP1b, have been linked to diet-induced obesity in mice (16, 17), but whether these molecules are dysregulated in common forms of human obesity is unknown.
Lessons Learned? Although leptin was named for its antiobesity effect in mice, evidence suggests that a major physiologic role of leptin is to signal energy deficiency to the brain and elicit hormonal, metabolic, and behavioral responses to restore energy stores (21, 22). Leptin levels fall rapidly during fasting and mediate the suppression of reproduction, thyroid hormone, and immune function (21). These defects are also seen in ob/ob mice with total leptin deficiency. Partial leptin deficiency leads to hypogonadism in starvation, hypothalamic amenorrhea, and lipodystrophy in humans (26). Thus, leptin has a broad dose-response range in mediating the response to starvation as leptin levels fall, as well as limiting overfeeding as the levels rise (20, 22). It is possible that leptin resistance confers an evolutionary advantage by promoting energy storage against the threat of starvation. Leptin has myriad effects on glucose and lipid metabolism, brain development, hematopoiesis, inflammation, bone biology, cellular growth and differentiation, and other biological systems, apart from energy homeostasis (7, 16). This happens often in endocrinology when a hormone is named initially for a presumed function and is found later to exert multiple effects. As an example, insulin has a major role in regulating glucose levels, but this is not the only function of insulin under normal or pathologic conditions. Insulin has diverse effects on lipid and protein metabolism, cell growth and differentiation, and other systems. Obesity is a highly complex disorder of energy metabolism that culminates in excessive fat accumulation in adipose, liver, skeletal muscle, and other organs. Obesity is influenced by genetic and environmental factors, particularly diet and exercise. Therefore, animal and cellular studies into obesity pathogenesis and drug discovery need to consider interactions of complex processes instead of simple linear pathways. The role of genetics in human obesity was recognized in twin studies many decades ago (27). The discovery of mutations associated with human obesity has illuminated our knowledge (28). Genetic loci
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identified in genome-wide association studies have been linked with obesity; however, the overall trait variance explained by these associated loci is very small, suggesting that most of the familial aggregation of obesity may be influenced by environmental modulation of epigenetic processes. The impact of intrauterine and postnatal environmental factors on the programming of metabolism is an exciting area for exploration. Another area that needs improvement is the assessment of body composition. Our current definition of obesity based on a threshold BMI value ignores population distribution patterns of weight and fat. The BMI is not a precise measure of fat, does not account for lean mass and fat location, and does not consider racial/ethnic and sex differences in fat content and distribution. Visceral fat and muscle mass are better predictors of insulin resistance, diabetes, and other metabolic disorders. Therefore, there is an urgent need for accurate and affordable methods for evaluating body composition in clinical and population studies (29). Our knowledge of the mechanisms linking obesity to the development of diabetes, cardiovascular disease, cancer, and other obesity-related diseases is rudimentary. It is well known that obesity is associated with insulin resistance and activation of innate immunity, but are they causally linked with a range of obesity-related diseases, such as diabetes, cancer, infertility, and osteoarthritis (30)? Can we harness information on adipokines, cytokines, and other biomarkers for diagnostic purposes in obesity or for the development of specific drugs for diseases associated with obesity? Despite the enormous progress in understanding of molecular mechanisms relating to weight loss, current dietary and medical interventions often fail to sustain long-term weight loss (31). Gastric bypass surgery, which is the most effective treatment of morbid obesity, rapidly reverses diabetes in the absence of substantial weight loss (32). These findings demand a rethinking of the treatment of obesity and related diseases. We need novel prevention and treatment strategies based on a better understanding of the biochemistry of macronutrients and micronutrients, energy metabolism, impact of lifestyle and environmental factors on homeostatic mechanisms, potential roles of endocrine disruptors and gut microbiota on metabolism, and multiple pathways linking genetics and the environment. Regardless of these vexing issues, it is safe to say that we have made tremendous strides in understanding metabolism and obesity. There is a broad of range of exciting research opportunities spanning cellular models, genetically modified animal models, patients with various genetic defects, and population studies. Molecular tools and
Mol Endocrinol, June 2014, 28(6):785–789
techniques are essential for unraveling the mysteries of energy metabolism, obesity, and disease pathogenesis. Molecular Endocrinology will continue to play a crucial role by providing the basic and translational research communities ample opportunities to disseminate their work. Rexford S. Ahima, MD, PhD Editor, Molecular Endocrinology
Acknowledgments Address all correspondence and requests for reprints to: Rexford S. Ahima, MD, PhD, University of Pennsylvania, Perelman School of Medicine, 12–104 Smilow Center for Translational Research, 3400 Civic Center, Building 421, Philadelphia, PA 19104. E-mail: [email protected]. This work was supported by the National Institute of Health (Grant P01-DK049210; P30-DK19525). Disclosure Summary: The author has nothing to disclose.
References 1. Coleman DL, Hummel KP. Effects of parabiosis of normal with genetically diabetic mice. Am J Physiol. 1969;217:1298 –1304. 2. Coleman DL. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia. 1973;9:294 –298. 3. Obesity and overweight. Fact sheet no. 311, 2013. World Health Organization website. http://www.who.int/mediacentre/factsheets/ fs311/en/. Accessed April 29, 2014. 4. Ahima RS. Digging deeper into obesity. J Clin Invest. 2011;121: 2076 –2079. 5. Adult obesity facts. Centers for Disease Control and Prevention website. http://www.cdc.gov/obesity/data/adult.html. Accessed April 29, 2014. 6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425– 432. 7. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21:263– 307. 8. Ingalls AM, Dickei MM, Snell GD. Obese, a new mutation in the house mouse. J Hered. 1950;41:317–318. 9. Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science. 1966;153:1127–1128. 10. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269: 543–546. 11. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546 –549. 12. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540 –543. 13. Tartaglia LA, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–1271. 14. Chua SC Jr, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science. 1996;271:994 –996. 15. Baumann H, et al. The full-length leptin receptor has signaling
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 September 2015. at 06:09 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/me.2014-1140
16. 17. 18.
19.
20. 21. 22.
23. 24.
capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci USA. 1996;93:8374 – 8378. Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70:537–556. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest. 2011;121:2087–2093. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–908. Clément K, Vaisse C, Lahlou N. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398 – 401. Flier JS. Clinical review 94: What’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab. 1998;83:1407–1413. Ahima RS, Prabakaran D, Mantzoros C. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250 –252. Ahima RS, Kelly J, Elmquist JK, Flier JS. Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia. Endocrinology. 1999;140:4923– 4931. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570 –578. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/meta-
mend.endojournals.org
25.
26.
27.
28. 29. 30.
31. 32.
789
bolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110:1093–1103. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282:1568 –1575. Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA, Mantzoros CS. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab. 2013;18:29 – 42. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The bodymass index of twins who have been reared apart. N Engl J Med. 1990;322:1483–1487. Ramachandrappa S, Farooqi IS. Genetic approaches to understanding human obesity. J Clin Invest. 2011;121:2080 –2086. Ahima RS, Lazar MA. Physiology. The health risk of obesity– better metrics imperative. Science. 2013;341:856 – 858. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18: 363–374. Bray GA, Ryan DH. Update on obesity pharmacotherapy. Ann NY Acad Sci. 2014;1311:1–13. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol. 2013;10:575– 584.
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