- Email: [email protected]
Leptin's Physiologic Role: Does the Emperor of Energy Balance Have No Clothes?
Cell Metabolism
Perspective Leptin’s Physiologic Role: Does the Emperor of Energy Balance Have No Clothes? Jeffrey S. Flier1,2,* and Eleftheria Maratos-Flier2 1Department
of Neurobiology, Harvard Medical School, 200 Longwood Avenue, Goldenson 542, Boston, MA 02215, USA of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2017.05.013 2Department
The discovery of the obese gene and the demonstration that its encoded protein leptin can reverse obesity due to genetic deficiency of the hormone were landmark discoveries in endocrinology and metabolism. Regarding leptin’s role in physiology, it is now established that falling leptin levels are a key signal of the starved state in mice and humans. Repleting leptin reverses the starvation signal both in physiologic starvation and in obesity resulting from genetic leptin deficiency. Since its discovery, it has also been hypothesized that rising leptin levels caused by overfeeding provide a physiologic signal that orchestrates resistance to obesity. Although still widely believed, and possibly true in some circumstances, this aspect of leptin physiology has not been experimentally demonstrated. It will be important to determine whether leptin or as yet undiscovered factors are responsible for the well-documented capacity for physiologic resistance to overfeeding. The identification of the obese gene in 1994 (Zhang et al., 1994) and the description of the key actions of its encoded protein leptin in 1995 (Campfield et al., 1995; Maffei et al., 1995) were landmark discoveries in endocrinology and metabolism. By employing genetics to discover a previously unknown fat-derived hormone that signals the state of energy stores to the brain, a new era in understanding the integrated control of energy balance was initiated. Demonstrations that recombinant leptin could reverse obesity due to genetic leptin deficiency in mice (Campfield et al., 1995; Maffei et al., 1995) and soon thereafter in humans (Farooqi et al., 1999) were powerful illustrations of what molecular medicine and biotechnology can accomplish together. However, leptin’s ability to reverse a state of its absolute deficiency reveals less than we need to know about the physiology of this hormone. The initial view of leptin, typically recounted in innumerable textbooks and reviews, describes its dominant role thus: as energy stores accumulate in fat, circulating leptin levels rise, feeding back to CNS control centers to limit obesity by reducing food intake and increasing energy expenditure (Friedman, 2002). According to this still prevalent view, leptin’s prime physiologic function is to promote leanness, explaining the selection of the name, from the Greek root leptos or thin. Soon after its discovery, it became evident that most obese people (Considine et al., 1996) and animals (Frederich et al., 1995a, 1995b) have high circulating levels of leptin. In the context of diet-related obesity, when given supplemental leptin by injection, both mice and humans respond to a very limited extent or not at all with reductions in food intake or body weight. Consistent with practice in the field, this phenomenon was initially termed leptin resistance (Frederich et al., 1995a), analogous to the well-described state of insulin resistance in type 2 diabetes and obesity. Resistance to leptin is in fact more marked than typical insulin resistance in diabetes, since in most insulin-resis24 Cell Metabolism 26, July 5, 2017 ª 2017 Elsevier Inc.
tant patients, simply increasing insulin levels lowers blood sugar, making it useful as a therapy for diabetes. In contrast, increasing leptin levels in obesity has to this point failed as a therapy for obesity (Heymsfield et al., 1999). In 1996, soon after its discovery, an alternative view of the function of leptin was proposed (Ahima et al., 1996). In this account, rather than acting as a hormone to limit obesity, it was proposed that the primary physiologic role of leptin was to provide a signal of energy deficit to the CNS (Ahima et al., 1996). According to this view, falling leptin levels initiate a homeostatic feedback loop that limits the energy deficit by increasing appetite, suppressing reproduction and thyroid hormone levels, as well as reducing energy expenditure. Strong support for this hypothesis was the demonstration in mice that leptin replacement during fasting that prevented leptin levels from falling prevented or attenuated the hormonal responses to fasting, including the suppression of reproductive cycling that occurs in energyrestricted females (Ahima et al., 1996). Key elements of this observation have been extended to humans. Specifically, women athletes with low adiposity, low leptin levels, and hypothalamic amenorrhea have their cycles restored by leptin administration (Welt et al., 2004). In addition, when leptin is administered to food-restricted subjects whose leptin levels have fallen, increases in energy expenditure are observed (Rosenbaum et al., 2005). These observations and others extended the initial findings in food-restricted mice and established experimentally that falling leptin levels are a physiologically critical starvation signal. A subsequent, albeit indirect, indication that lower than ‘‘normal’’ leptin levels on a chronic basis may promote obesity is the observation that humans heterozygous for leptin deficiency have reduced leptin levels and modestly increased fat mass (Farooqi et al., 2001). Reduction in fat mass after leptin administration in such subjects might be expected but has not been reported.
Cell Metabolism
Perspective While reviews of leptin physiology typically reference this role of leptin as a starvation signal, they also typically state that leptin levels increase as fat stores rise, thereby signaling the CNS to resist weight gain by decreasing appetite and increasing energy expenditure. How well supported is this claim? In one study of non-obese humans whose leptin levels were markedly raised over 6 days, no changes in autonomic activity or other metabolic parameters were seen, and appetite was not assessed (Mackintosh and Hirsch, 2001). We were unable to find other convincing experiments demonstrating an anti-obesity effect of leptin via suppression of appetite or enhanced energy expenditure in humans who express leptin. To consider what research might have been conducted to understand leptin physiology, insulin can serve as an example. Insulin was discovered in 1922 as a factor that could reverse diabetes in people with type 1 diabetes, a disorder later learned to be due to insulin deficiency caused by autoimmunity directed at insulin-producing b cells. Insulin was a transformative therapeutic for a previously fatal disease. In innumerable subsequent papers, researchers administered insulin to non-diabetic individuals to determine its role in normal physiology. It did not take long to show that insulin lowers blood glucose levels in non-diabetic humans. By combining techniques to measure insulin levels with assessment of inter-organ metabolic fluxes in response to its administration, the complex role of insulin in metabolic physiology in healthy humans has been extensively defined. How does this compare with leptin, discovered 72 years after insulin, at a time when techniques for assessing physiology are far more advanced and available? Unfortunately, nothing similar has been accomplished with leptin in humans. An experiment to test the hypothesis that rising leptin in response to overfeeding acts as a signal of increased energy stores, instructing the CNS to initiate resistance to weight gain might be conducted as follows. Take individuals of normal weight who achieve this without restricting food intake by dieting, that is, individuals in whom leptin might be hypothesized to be working well as an ‘‘adipostatic’’ anti-obesity signal. Observe them with baseline measurements, including hunger scores, freely chosen food intake, fat mass, and energy expenditure among others parameters. Then administer leptin (or placebo) to produce leptin levels above baseline for several days or weeks, while continuing observations and metabolic measurements. If the hypothesis that leptin is an anti-obesity signal is correct, these individuals should respond to increased leptin with reduced hunger, reduced food ingestion, increased energy expenditure, and loss of fat mass. Such results would verify the hypothesis that leptin orchestrates resistance to obesity by its levels rising in non-obese individuals with a fully operative ‘‘adipostat.’’ The results would also provide critical information on the dose-response and physiologic mechanisms by which it does so. Why might such individuals not respond in this way, in contrast to this hypothesis? Leptin levels might indeed be preventing obesity in such naturally lean individuals, but doing so at the maximal biologic dose response for this action, with additional leptin incapable of acting beyond the prevailing level. Although possible, this would be a highly unusual dose-response relationship for any physiologic hormonal system of which we are aware, where ‘‘supra-physiologic’’ actions beyond those prevailing in
healthy individuals create disorders of hormone excess. Such an atypical outcome could be due to receptor saturation at prevailing levels, or engagement of cellular factors, such as SOCS3 (Bjorbaek et al., 1998) that suppress leptin signaling in key sites of action. Failure to respond to increased levels, whatever the molecular cause, might suggest that while a minimal level of leptin is surely needed to avoid the massive obesity in totally leptindeficient individuals, further enhancing leptin action beyond that minimal threshold is not responsible for avoidance of obesity, or distinguishing naturally lean individuals from the obese. It is possible that an as yet undiscovered regulatory molecule could be responsible for mediating resistance to obesity in response to overfeeding, since indeed there is substantial physiologic evidence for this in both experimental animals and humans (Ravussin et al., 2014). If such a system existed, dysfunction of that system might explain why some individuals are lean and others are obese. That resistance to obesity in response to overfeeding may be mediated by such an as yet undiscovered factor was hypothesized several years ago (Ravussin et al., 2014), but today, the existence of such a factor remains unknown. It is surprising that studies of leptin physiology in normal individuals are so limited 23 years after its discovery. This makes it difficult to understand leptin physiology in humans or the mechanism and significance of leptin resistance, an important topic on which many papers have been published. A recent consensus panel lamented the lack of specificity of the term ‘‘leptin resistance’’ as used today, mainly because of the near total lack of experimental evidence in humans on which to base use of the term (Myers et al., 2012). Harking back to insulin, our understanding of insulin action and resistance in obesity and type 2 diabetes rests on thousands of studies of insulin biologic dose responses on dozens of metabolic pathways. Together, these studies reveal that insulin resistance is a complex concept, with highly diverse consequences for different physiologic and signaling pathways. There is no single meaning of the term ‘‘insulin resistance.’’ With leptin, lacking any studies of its dose responsive biologic actions in normal humans, the nature of ‘‘leptin resistance’’ in human obesity has, not surprisingly, been impossible to define. Within a year of its discovery, several companies produced recombinant leptin or leptin analogs for studies in animals and man. One of these, Amgen, licensed the leptin patent from Rockefeller University and the Howard Hughes Medical Institute. Numerous investigators were eager to conduct studies to elucidate the physiology of leptin. Amgen was apparently willing to provide leptin to a limited number of external scientists to undertake investigator-initiated studies of leptin physiology (A. DePaoli, personal communication). If so, why were so few such studies published? Here, we can only speculate. Amgen was focused on successfully developing leptin as a treatment for obesity and obesity-linked diabetes, two huge and medically important markets. The company may initially have been concerned that allowing academic scientists to investigate the biology of leptin at that early stage might produce results that would slow its development path toward this huge market. Then, when initial results on efficacy of leptin in treating obesity proved disappointing, support for an exploratory leptin program within Amgen collapsed, and funds for external exploratory Cell Metabolism 26, July 5, 2017 25
Cell Metabolism
Perspective physiologic studies also rapidly disappeared. Despite the potential availability of recombinant leptin at that time, NIH interest in supporting such studies appeared to be limited, and investigators moved on to other topics. Today, there is limited or no availability of leptin for clinical research studies of the kind I describe. Rights to leptin have passed to progressively smaller companies. It is now approved for administration in extremely rare patients with genetic leptin deficiency or leptin deficiency secondary to rare forms of lipoatrophic diabetes (Oral et al., 2002). As a consequence, 23 years after its discovery, in addition to lacking leptin as therapy for a subset of patients with common forms of obesity, we also lack any reasonable mechanistic understanding of why leptin treatment of obesity failed. We also have an extremely limited understanding of the physiology of the hormone apart from its role as a starvation signal. Perhaps, if translational investigators had conducted hypothesis-generating experiments in humans, they may have uncovered unknown actions of leptin and novel approaches to its successful use in obesity or other disorders. In the end, what we find most surprising is the extent to which scientists in the field of metabolism and energy balance seem unaware or even unconcerned that key experiments, such as those we have described, were never reported. Articles, reviews, and chapters on leptin continue to recite the mantra that leptin mediates resistance to obesity by its levels rising (in some subjects) in response to positive energy balance. Unfortunately, as discussed above, this proposed and widely accepted ‘‘antiobesity limb’’ of leptin physiology has never been clearly demonstrated to be present in man. While some leptin is clearly necessary to prevent obesity, the physiologic role of leptin in most individuals may be limited to signaling the response to energy deficiency, and then reversing that signal as energy stores are repleted, as first hypothesized in 1996 (Ahima et al., 1996; Flier, 1998). If so, the biology of leptin has little to do with leanness or obesity apart from those rare cases of primary deficiency with severe obesity. Despite the foregoing discussion, we continue to believe that healthy and lean individuals exist who resist obesity at least in part through their leptin levels rising in response to positive energy balance, evoking homeostatic changes in food intake and energy expenditure via increased leptin action. We also believe that some individuals develop obesity because they insufficiently enhance leptin action in response to positive energy balance, either due to insufficiently elevated leptin levels or cellular resistance to leptin at one or more sites of action. But believing this is distinct from knowing it to be true. It is possible that as yet undiscovered molecules, not leptin, account for this physiologic regulation and dysregulation in obesity. Before we write the next generation of chapters and reviews of leptin physiology and obesity, we should commit to seeing that these important questions are finally answered. REFERENCES Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., and Flier, J.S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252.
26 Cell Metabolism 26, July 5, 2017
Bjorbaek, C., Elmquist, J.K., Frantz, J.D., Shoelson, S.E., and Flier, J.S. (1998). Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625. Campfield, L.A., Smith, F.J., Guisez, Y., Devos, R., and Burn, P. (1995). Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549. Considine, R.V., Sinha, M.K., Heiman, M.L., Kriauciunas, A., Stephens, T.W., Nyce, M.R., Ohannesian, J.P., Marco, C.C., McKee, L.J., Bauer, T.L., et al. (1996). Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295. Farooqi, I.S., Jebb, S.A., Langmack, G., Lawrence, E., Cheetham, C.H., Prentice, A.M., Hughes, I.A., McCamish, M.A., and O’Rahilly, S. (1999). Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884. Farooqi, I.S., Keogh, J.M., Kamath, S., Jones, S., Gibson, W.T., Trussell, R., Jebb, S.A., Lip, G.Y., and O’Rahilly, S. (2001). Partial leptin deficiency and human adiposity. Nature 414, 34–35. Flier, J.S. (1998). Clinical review 94: what’s in a name? In search of leptin’s physiologic role. J. Clin. Endocrinol. Metab. 83, 1407–1413. Frederich, R.C., Hamann, A., Anderson, S., Lollmann, B., Lowell, B.B., and Flier, J.S. (1995a). Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314. Frederich, R.C., Lollmann, B., Hamann, A., Napolitano-Rosen, A., Kahn, B.B., Lowell, B.B., and Flier, J.S. (1995b). Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J. Clin. Invest. 96, 1658–1663. Friedman, J.M. (2002). The function of leptin in nutrition, weight, and physiology. Nutr. Rev. 60, S1–S14, discussion S68–84, 85–7. Heymsfield, S.B., Greenberg, A.S., Fujioka, K., Dixon, R.M., Kushner, R., Hunt, T., Lubina, J.A., Patane, J., Self, B., Hunt, P., et al. (1999). Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282, 1568–1575. Mackintosh, R.M., and Hirsch, J. (2001). The effects of leptin administration in non-obese human subjects. Obes. Res. 9, 462–469. Maffei, M., Halaas, J., Ravussin, E., Pratley, R.E., Lee, G.H., Zhang, Y., Fei, H., Kim, S., Lallone, R., Ranganathan, S., et al. (1995). Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weightreduced subjects. Nat. Med. 1, 1155–1161. Myers, M.G., Jr., Heymsfield, S.B., Haft, C., Kahn, B.B., Laughlin, M., Leibel, R.L., Tschop, M.H., and Yanovski, J.A. (2012). Challenges and opportunities of defining clinical leptin resistance. Cell Metab. 15, 150–156. Oral, E.A., Simha, V., Ruiz, E., Andewelt, A., Premkumar, A., Snell, P., Wagner, A.J., DePaoli, A.M., Reitman, M.L., Taylor, S.I., et al. (2002). Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578. Ravussin, Y., Leibel, R.L., and Ferrante, A.W., Jr. (2014). A missing link in body weight homeostasis: the catabolic signal of the overfed state. Cell Metab. 20, 565–572. Rosenbaum, M., Goldsmith, R., Bloomfield, D., Magnano, A., Weimer, L., Heymsfield, S., Gallagher, D., Mayer, L., Murphy, E., and Leibel, R.L. (2005). Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579–3586. Welt, C.K., Chan, J.L., Bullen, J., Murphy, R., Smith, P., DePaoli, A.M., Karalis, A., and Mantzoros, C.S. (2004). Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987–997. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.
Perspective Leptin’s Physiologic Role: Does the Emperor of Energy Balance Have No Clothes? Jeffrey S. Flier1,2,* and Eleftheria Maratos-Flier2 1Department
of Neurobiology, Harvard Medical School, 200 Longwood Avenue, Goldenson 542, Boston, MA 02215, USA of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2017.05.013 2Department
The discovery of the obese gene and the demonstration that its encoded protein leptin can reverse obesity due to genetic deficiency of the hormone were landmark discoveries in endocrinology and metabolism. Regarding leptin’s role in physiology, it is now established that falling leptin levels are a key signal of the starved state in mice and humans. Repleting leptin reverses the starvation signal both in physiologic starvation and in obesity resulting from genetic leptin deficiency. Since its discovery, it has also been hypothesized that rising leptin levels caused by overfeeding provide a physiologic signal that orchestrates resistance to obesity. Although still widely believed, and possibly true in some circumstances, this aspect of leptin physiology has not been experimentally demonstrated. It will be important to determine whether leptin or as yet undiscovered factors are responsible for the well-documented capacity for physiologic resistance to overfeeding. The identification of the obese gene in 1994 (Zhang et al., 1994) and the description of the key actions of its encoded protein leptin in 1995 (Campfield et al., 1995; Maffei et al., 1995) were landmark discoveries in endocrinology and metabolism. By employing genetics to discover a previously unknown fat-derived hormone that signals the state of energy stores to the brain, a new era in understanding the integrated control of energy balance was initiated. Demonstrations that recombinant leptin could reverse obesity due to genetic leptin deficiency in mice (Campfield et al., 1995; Maffei et al., 1995) and soon thereafter in humans (Farooqi et al., 1999) were powerful illustrations of what molecular medicine and biotechnology can accomplish together. However, leptin’s ability to reverse a state of its absolute deficiency reveals less than we need to know about the physiology of this hormone. The initial view of leptin, typically recounted in innumerable textbooks and reviews, describes its dominant role thus: as energy stores accumulate in fat, circulating leptin levels rise, feeding back to CNS control centers to limit obesity by reducing food intake and increasing energy expenditure (Friedman, 2002). According to this still prevalent view, leptin’s prime physiologic function is to promote leanness, explaining the selection of the name, from the Greek root leptos or thin. Soon after its discovery, it became evident that most obese people (Considine et al., 1996) and animals (Frederich et al., 1995a, 1995b) have high circulating levels of leptin. In the context of diet-related obesity, when given supplemental leptin by injection, both mice and humans respond to a very limited extent or not at all with reductions in food intake or body weight. Consistent with practice in the field, this phenomenon was initially termed leptin resistance (Frederich et al., 1995a), analogous to the well-described state of insulin resistance in type 2 diabetes and obesity. Resistance to leptin is in fact more marked than typical insulin resistance in diabetes, since in most insulin-resis24 Cell Metabolism 26, July 5, 2017 ª 2017 Elsevier Inc.
tant patients, simply increasing insulin levels lowers blood sugar, making it useful as a therapy for diabetes. In contrast, increasing leptin levels in obesity has to this point failed as a therapy for obesity (Heymsfield et al., 1999). In 1996, soon after its discovery, an alternative view of the function of leptin was proposed (Ahima et al., 1996). In this account, rather than acting as a hormone to limit obesity, it was proposed that the primary physiologic role of leptin was to provide a signal of energy deficit to the CNS (Ahima et al., 1996). According to this view, falling leptin levels initiate a homeostatic feedback loop that limits the energy deficit by increasing appetite, suppressing reproduction and thyroid hormone levels, as well as reducing energy expenditure. Strong support for this hypothesis was the demonstration in mice that leptin replacement during fasting that prevented leptin levels from falling prevented or attenuated the hormonal responses to fasting, including the suppression of reproductive cycling that occurs in energyrestricted females (Ahima et al., 1996). Key elements of this observation have been extended to humans. Specifically, women athletes with low adiposity, low leptin levels, and hypothalamic amenorrhea have their cycles restored by leptin administration (Welt et al., 2004). In addition, when leptin is administered to food-restricted subjects whose leptin levels have fallen, increases in energy expenditure are observed (Rosenbaum et al., 2005). These observations and others extended the initial findings in food-restricted mice and established experimentally that falling leptin levels are a physiologically critical starvation signal. A subsequent, albeit indirect, indication that lower than ‘‘normal’’ leptin levels on a chronic basis may promote obesity is the observation that humans heterozygous for leptin deficiency have reduced leptin levels and modestly increased fat mass (Farooqi et al., 2001). Reduction in fat mass after leptin administration in such subjects might be expected but has not been reported.
Cell Metabolism
Perspective While reviews of leptin physiology typically reference this role of leptin as a starvation signal, they also typically state that leptin levels increase as fat stores rise, thereby signaling the CNS to resist weight gain by decreasing appetite and increasing energy expenditure. How well supported is this claim? In one study of non-obese humans whose leptin levels were markedly raised over 6 days, no changes in autonomic activity or other metabolic parameters were seen, and appetite was not assessed (Mackintosh and Hirsch, 2001). We were unable to find other convincing experiments demonstrating an anti-obesity effect of leptin via suppression of appetite or enhanced energy expenditure in humans who express leptin. To consider what research might have been conducted to understand leptin physiology, insulin can serve as an example. Insulin was discovered in 1922 as a factor that could reverse diabetes in people with type 1 diabetes, a disorder later learned to be due to insulin deficiency caused by autoimmunity directed at insulin-producing b cells. Insulin was a transformative therapeutic for a previously fatal disease. In innumerable subsequent papers, researchers administered insulin to non-diabetic individuals to determine its role in normal physiology. It did not take long to show that insulin lowers blood glucose levels in non-diabetic humans. By combining techniques to measure insulin levels with assessment of inter-organ metabolic fluxes in response to its administration, the complex role of insulin in metabolic physiology in healthy humans has been extensively defined. How does this compare with leptin, discovered 72 years after insulin, at a time when techniques for assessing physiology are far more advanced and available? Unfortunately, nothing similar has been accomplished with leptin in humans. An experiment to test the hypothesis that rising leptin in response to overfeeding acts as a signal of increased energy stores, instructing the CNS to initiate resistance to weight gain might be conducted as follows. Take individuals of normal weight who achieve this without restricting food intake by dieting, that is, individuals in whom leptin might be hypothesized to be working well as an ‘‘adipostatic’’ anti-obesity signal. Observe them with baseline measurements, including hunger scores, freely chosen food intake, fat mass, and energy expenditure among others parameters. Then administer leptin (or placebo) to produce leptin levels above baseline for several days or weeks, while continuing observations and metabolic measurements. If the hypothesis that leptin is an anti-obesity signal is correct, these individuals should respond to increased leptin with reduced hunger, reduced food ingestion, increased energy expenditure, and loss of fat mass. Such results would verify the hypothesis that leptin orchestrates resistance to obesity by its levels rising in non-obese individuals with a fully operative ‘‘adipostat.’’ The results would also provide critical information on the dose-response and physiologic mechanisms by which it does so. Why might such individuals not respond in this way, in contrast to this hypothesis? Leptin levels might indeed be preventing obesity in such naturally lean individuals, but doing so at the maximal biologic dose response for this action, with additional leptin incapable of acting beyond the prevailing level. Although possible, this would be a highly unusual dose-response relationship for any physiologic hormonal system of which we are aware, where ‘‘supra-physiologic’’ actions beyond those prevailing in
healthy individuals create disorders of hormone excess. Such an atypical outcome could be due to receptor saturation at prevailing levels, or engagement of cellular factors, such as SOCS3 (Bjorbaek et al., 1998) that suppress leptin signaling in key sites of action. Failure to respond to increased levels, whatever the molecular cause, might suggest that while a minimal level of leptin is surely needed to avoid the massive obesity in totally leptindeficient individuals, further enhancing leptin action beyond that minimal threshold is not responsible for avoidance of obesity, or distinguishing naturally lean individuals from the obese. It is possible that an as yet undiscovered regulatory molecule could be responsible for mediating resistance to obesity in response to overfeeding, since indeed there is substantial physiologic evidence for this in both experimental animals and humans (Ravussin et al., 2014). If such a system existed, dysfunction of that system might explain why some individuals are lean and others are obese. That resistance to obesity in response to overfeeding may be mediated by such an as yet undiscovered factor was hypothesized several years ago (Ravussin et al., 2014), but today, the existence of such a factor remains unknown. It is surprising that studies of leptin physiology in normal individuals are so limited 23 years after its discovery. This makes it difficult to understand leptin physiology in humans or the mechanism and significance of leptin resistance, an important topic on which many papers have been published. A recent consensus panel lamented the lack of specificity of the term ‘‘leptin resistance’’ as used today, mainly because of the near total lack of experimental evidence in humans on which to base use of the term (Myers et al., 2012). Harking back to insulin, our understanding of insulin action and resistance in obesity and type 2 diabetes rests on thousands of studies of insulin biologic dose responses on dozens of metabolic pathways. Together, these studies reveal that insulin resistance is a complex concept, with highly diverse consequences for different physiologic and signaling pathways. There is no single meaning of the term ‘‘insulin resistance.’’ With leptin, lacking any studies of its dose responsive biologic actions in normal humans, the nature of ‘‘leptin resistance’’ in human obesity has, not surprisingly, been impossible to define. Within a year of its discovery, several companies produced recombinant leptin or leptin analogs for studies in animals and man. One of these, Amgen, licensed the leptin patent from Rockefeller University and the Howard Hughes Medical Institute. Numerous investigators were eager to conduct studies to elucidate the physiology of leptin. Amgen was apparently willing to provide leptin to a limited number of external scientists to undertake investigator-initiated studies of leptin physiology (A. DePaoli, personal communication). If so, why were so few such studies published? Here, we can only speculate. Amgen was focused on successfully developing leptin as a treatment for obesity and obesity-linked diabetes, two huge and medically important markets. The company may initially have been concerned that allowing academic scientists to investigate the biology of leptin at that early stage might produce results that would slow its development path toward this huge market. Then, when initial results on efficacy of leptin in treating obesity proved disappointing, support for an exploratory leptin program within Amgen collapsed, and funds for external exploratory Cell Metabolism 26, July 5, 2017 25
Cell Metabolism
Perspective physiologic studies also rapidly disappeared. Despite the potential availability of recombinant leptin at that time, NIH interest in supporting such studies appeared to be limited, and investigators moved on to other topics. Today, there is limited or no availability of leptin for clinical research studies of the kind I describe. Rights to leptin have passed to progressively smaller companies. It is now approved for administration in extremely rare patients with genetic leptin deficiency or leptin deficiency secondary to rare forms of lipoatrophic diabetes (Oral et al., 2002). As a consequence, 23 years after its discovery, in addition to lacking leptin as therapy for a subset of patients with common forms of obesity, we also lack any reasonable mechanistic understanding of why leptin treatment of obesity failed. We also have an extremely limited understanding of the physiology of the hormone apart from its role as a starvation signal. Perhaps, if translational investigators had conducted hypothesis-generating experiments in humans, they may have uncovered unknown actions of leptin and novel approaches to its successful use in obesity or other disorders. In the end, what we find most surprising is the extent to which scientists in the field of metabolism and energy balance seem unaware or even unconcerned that key experiments, such as those we have described, were never reported. Articles, reviews, and chapters on leptin continue to recite the mantra that leptin mediates resistance to obesity by its levels rising (in some subjects) in response to positive energy balance. Unfortunately, as discussed above, this proposed and widely accepted ‘‘antiobesity limb’’ of leptin physiology has never been clearly demonstrated to be present in man. While some leptin is clearly necessary to prevent obesity, the physiologic role of leptin in most individuals may be limited to signaling the response to energy deficiency, and then reversing that signal as energy stores are repleted, as first hypothesized in 1996 (Ahima et al., 1996; Flier, 1998). If so, the biology of leptin has little to do with leanness or obesity apart from those rare cases of primary deficiency with severe obesity. Despite the foregoing discussion, we continue to believe that healthy and lean individuals exist who resist obesity at least in part through their leptin levels rising in response to positive energy balance, evoking homeostatic changes in food intake and energy expenditure via increased leptin action. We also believe that some individuals develop obesity because they insufficiently enhance leptin action in response to positive energy balance, either due to insufficiently elevated leptin levels or cellular resistance to leptin at one or more sites of action. But believing this is distinct from knowing it to be true. It is possible that as yet undiscovered molecules, not leptin, account for this physiologic regulation and dysregulation in obesity. Before we write the next generation of chapters and reviews of leptin physiology and obesity, we should commit to seeing that these important questions are finally answered. REFERENCES Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., and Flier, J.S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252.
26 Cell Metabolism 26, July 5, 2017
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