sign in sign up
<<
Home , Dieting

Revisiting ’s role in and

Rexford S. Ahima

J Clin Invest. 2008;118(7):2380-2383. https://doi.org/10.1172/JCI36284.

Commentary

Maintenance of weight loss is often unsuccessful because of metabolic adaptations that conserve energy. Studies in rodents suggest that a reduction in leptin level during weight loss signals to the brain to increase feeding and decrease energy expenditure. In this issue of the JCI, Rosenbaum et al. examined this concept in obese patients who lost weight and were maintained at 10% below their initial weight (see the related article beginning on page 2583). Brain activity responses to visual stimuli were visualized using functional MRI. Leptin levels fell during weight loss and increased brain activity in areas involved in emotional, cognitive, and sensory control of food intake. Restoration of leptin levels maintained weight loss and reversed the changes in brain activity. Thus, leptin is a critical factor linking reduced energy stores to behavior. Potentially, leptin could sustain weight loss by overriding the tendency toward energy conservation.

Find the latest version: https://jci.me/36284/pdf Commentaries Revisiting leptin’s role in obesity and weight loss Rexford S. Ahima

Department of Medicine, Division of Endocrinology, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Maintenance of weight loss is often unsuccessful because of metabolic onstrated that leptin is transported into adaptations that conserve energy. Studies in rodents suggest that a reduc- the brain, binds to its receptor in the hypo- tion in leptin level during weight loss signals to the brain to increase thalamus, and activates JAK-STAT3, lead- feeding and decrease energy expenditure. In this issue of the JCI, Rosen- ing to suppression of “orexigenic peptides” baum et al. examined this concept in obese patients who lost weight and (e.g., neuropeptide Y and agouti-related were maintained at 10% below their initial weight (see the related article protein, which normally increase food beginning on page 2583). Brain activity responses to visual food stimuli intake), and increase in “anorexigenic pep- were visualized using functional MRI. Leptin levels fell during weight tides” (e.g., proopiomelanocortin and cor- loss and increased brain activity in areas involved in emotional, cog- ticotrophin-releasing hormone, which nor- nitive, and sensory control of food intake. Restoration of leptin levels mally decrease food intake) (3). Although maintained weight loss and reversed the changes in brain activity. Thus, there is no obvious defect of leptin recep- leptin is a critical factor linking reduced energy stores to eating behavior. tors in -induced obese rodents, the Potentially, leptin therapy could sustain weight loss by overriding the transport of leptin across the blood-brain tendency toward energy conservation. barrier is diminished and levels of SOCS3, an inhibitor of leptin signaling, is increased Obesity results from an imbalance between bolic rate, which promote energy conser- in the hypothalamus (3, 6). However, it food intake and energy expenditure, cul- vation and regain of weight. In the current is unknown whether these factors are minating in excessive accumulation of issue of the JCI, Rosenbaum et al. describe involved in “common” (diet-induced; poly- in , liver, muscle, pan- specific patterns of brain activity in the genic) obesity in humans. creatic islets, and other organs involved cerebral cortex, limbic areas, and hypo- Leptin levels fall rapidly in response to in metabolism. Obesity increases the risk thalamus when weight-reduced patients and evoke profound changes in of diabetes, coronary artery disease, fatty were presented with visual food stimuli energy balance and hormone levels (5, liver, gall stones, , arthritis, (4). Interestingly, restoration of leptin to 6). Low leptin levels induce overfeeding and cancer and may shorten the lifespan pre–weight loss levels reversed the changes and suppress energy expenditure, thyroid (1). Our knowledge of the neurobiology in brain activity while preventing weight and reproductive hormones, and immu- of feeding and energy has regain. Thus, in addition to controlling nity (5, 8–10). In rodents, low leptin levels benefited from the discovery of fat- and hypothalamic neuronal circuits, metabol- increase levels of orexigenic peptides and gut-derived hormones and their targets ic signals such as leptin may entrain the reduce levels of anorexigenic peptides in the hypothalamus (2, 3) (Figure 1). perception of food through unexpected (3, 5). Leptin replacement reverses these However, eating is a complex behavior effects on the processing of visual and alterations in metabolism, immunity, and that is determined not only by conscious other sensory information. levels of hormones and hypothalamic neu- decision-making, but is also subject to ropeptides (5, 8–10). Moreover, restoration environmental factors such as the avail- Leptin’s ups and downs of leptin in patients lacking fat cells (lipo- ability and properties of food and social Leptin is secreted by fat cells (), dystrophy) improves reproductive func- and cultural norms. A greater under- and was originally thought to signal to the tion and reverses abnormal lipid and glu- standing of how brain areas involved in brain to inhibit food intake and decrease cose metabolism (11, 12). Together, these reward, cognition, and executive control weight (2, 5). This concept was partly studies demonstrate that the dominant of feeding can override metabolic regu- driven by the observation that humans role of leptin is to signal energy deficiency lation will facilitate the prevention and and rodents lacking a functional leptin in the brain (6). Teleologically, the adap- treatment of obesity. protein or receptor manifested voracious tations mediated by reduced leptin levels Caloric restriction is a logical strategy feeding and obesity (2). As was predicted, may have evolved as a protection against for weight reduction, but cannot be sus- leptin treatment, particularly direct injec- the threat of by limiting energy tained in the long term partly because of tion of leptin into the cerebral ventricle or use and enhancing energy storage in the increased and reduction in meta- hypothalamus, profoundly inhibited food form of fat (5, 6). In the modern environ- intake and decreased weight and fat in ani- ment, where food is plentiful and mals lacking leptin (2, 3, 6). However, the is sparse, this metabolic efficiency predis- Nonstandard abbreviations used: BOLD, blood oxy- gen level–dependent. notion of leptin as an anti-obesity hormone poses toward obesity. Conflict of interest: The author has received research was called into question because obesity is In earlier studies, Rosenbaum et al. exam- support from Biomeasure/Ipsen Inc. and served on typically associated with high leptin levels ined the concept that leptin is a critical scientific advisory boards of Bristol-Myers Squibb Co., and not leptin deficiency (6, 7). Moreover, signal for metabolic alterations induced Biomeasure/Ipsen Inc., and Ethicon Endo-Surgery (Johnson & Johnson). rodents and humans that become obese on by caloric restriction in humans (13, 14). Citation for this article: J. Clin. Invest. 118:2380–2383 a high-fat (Western) diet do not respond to Obese subjects were fed a to (2008). doi:10.1172/JCI36284. leptin (6, 7). In rodents, studies have dem- maintain their usual weight for several

2380 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 7 July 2008 commentaries

Figure 1 Schematic illustration of peptides secreted by the gut and adipose tissue (fat) that control energy balance. Ghrelin is produced in the stomach and is a potent stimulator of appetite in the brain. In addition to increasing the uptake of by muscle, liver, and fat, insulin acts in the brain to suppress food intake. Gut-derived peptides such as GLP-1 augment insulin release from the pancreas. Leptin levels decline during weight loss and signal to the hypothalamus to stimulate feeding, reduce energy expenditure, and promote weight regain. As Rosenbaum et al. demonstrate in this issue of the JCI (4), low leptin levels during weight loss also increase the activity of brain areas involved in the decision-making and reward aspects of eating behavior. Thus, preventing the decline of leptin levels during weight loss by hormone replacement may be a means of over- riding the homeostatic and behavioral tendencies toward energy conservation and weight regain during dieting. Image modified with permission from Gastroenterology (23). CCK, cholecystokinin; GLP-1, glucagon-like peptide–1; GRP, gastrin-releasing peptide; NMB, neuromedin B; OXY, oxyntomodulin; PAI-1, plasminogen activator inhibitor 1; PP, pancreatic polypeptide; PYY, peptide YY; RBP4, retinol-binding protein–4.

weeks, or were fed a reduced-calorie liquid the gut and fat, these studies do not address processes food stimuli (4). The authors diet to maintain a 10% reduction in weight. the cognitive and emotional aspects of eat- hypothesized that the weight-reduced The hypothesis was that a decrease in leptin ing behavior (3, 5, 6). Appetite is a subjective state is perceived by the brain as a state levels in the weight-reduced state would feeling of the motivation to eat. Hunger, of relative leptin deficiency, which evokes reduce energy expenditure and promote satiety, and satiation can be overridden by specific patterns of brain activity when weight regain. Leptin hormone replace- desire. Our food preferences and eating pat- individuals are presented with visual food ment prevented the decline in plasma leptin terns are molded by past experiences and stimuli. Leptin replacement to individuals level and restored energy expenditure by also influenced by sight, smell, and taste in the weight-reduced state was predicted increasing work efficiency, sensations. Eating behavior involves a com- to reverse brain activity to patterns simi- sympathetic nervous system tone, and thy- plex interaction between psychological and lar to the obese (pre–weight loss) state. By roid hormone to pre–weight loss levels (13, physiological processes that cannot be ade- delineating these differences, the authors 14). These changes were associated with quately explored in animal models. Humans hoped to gain insights into how meta- maintenance of weight reduction (13, 14). provide the appropriate model for address- bolic signals produced by fat affect eat- ing how sensory and hormonal signals inter- ing behavior. The experimental design Imaging leptin activity in human act to produce subjective and physiological was identical to previous studies (13, 14). brain changes in energy metabolism. Obese subjects underwent caloric restric- Although studies in animals have unraveled The study by Rosenbaum et al. in this tion, were maintained at 10% lower than circuits in the hypothalamus and brainstem issue of the JCI is an important contribu- their initial weight, and received replace- that are influenced by peptides derived from tion in elucidating how the ment doses of leptin or placebo in a cross-

The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 7 July 2008 2381 commentaries over design (research design in which sub- ity to suppress activity in the striatum, a Of mice and humans jects receive both treatments in sequence region involved in the pleasure and reward These elegant and inherently difficult so that, in effect, each individual serves responses to food (15). Baicy et al. observed studies by Rosenbaum et al. and others as his/her own control) for 5 weeks. Brain that leptin replacement decreased food highlight the potential of clinical investi- activity elicited by viewing food and non- intake and weight, and this was associ- gation (4, 13, 14–16). More than a decade food visual stimuli was monitored using ated with reduced brain activity in regions after the discovery of leptin (2), we now functional MRI (fMRI). This technique related to hunger (16). On the other hand, have studies exploring the activity of this measures blood oxygen level–dependent leptin increased brain activity in areas metabolic hormone in the human brain. (BOLD) signals and is based on the princi- linked to satiety (16). There is a tendency to label clinical stud- ple that deoxyhemoglobin concentration ies as “descriptive” or “lacking in mecha- in the blood supply decreases upon acti- Implications for obesity therapy nism.” To the contrary, the experiments vation of a group of neurons. The decline The earlier studies of Rosenbaum et al. outlined above are based on well-thought- in deoxyhemoglobin is visualized as a high revealed that leptin deficiency promoted out hypotheses, ingenious methodology, signal intensity when a T2-weighted image weight regain by stimulating appetite and and cogent interpretation of data. Above is obtained under high magnetic field and reducing energy output (13, 14). In the all, the results are applicable in humans. speed. BOLD signal is not reflective of current study, the decline in leptin served There is no doubt that animal models, in the electrical activity of neurons. Rather, as a key metabolic signal to modulate the particular mice, have advanced our knowl- BOLD is determined by the amount of reward and executive control of visual edge of molecular genetics and facilitated deoxyhemoglobin, which in turn depends food stimuli (4) (Figure 1). The ability of preclinical experimentation. But lest we on regional blood volume, blood flow, and leptin replacement to reverse these chang- forget, mice are not human! In fact, there oxygen consumption. es suggests that leptin itself or drugs that are numerous instances in which animal Rosenbaum et al. present a thorough stimulate leptin signaling may facilitate models based on inappropriate conceptual description of brain activity under differ- the maintenance of weight loss. Indeed, paradigms have led to spectacular failures ent weight conditions and leptin levels (4). leptin replacement augmented the effect and actually hindered medical discovery. At the initial weight, visual food stimuli of a weight loss drug, , in diet- Given the recent clamoring for “bench-to- induced activity in brain areas involved induced obese rats by further decreasing bedside” investigation, it is gratifying to in , autonomic and food intake and stimulating see the well-deserved publication of clini- hormonal regulation, as well as emotional oxidation (17). Likewise, it is possible cal/patient-oriented research (4, 15, 16, and executive control of eating behavior. that preventing the decline in leptin level, 22). This trend will undoubtedly encour- The hypothalamus, amygdala, hippo- via hormone replacement, could sustain age further research on obesity and meta- campus, parahippocampal and cingulate the effects of dieting or drug treatment in bolic disorders. gyri, and frontal and parietal cortex all obese patients. showed increased activity. In contrast, the Another area that deserves further Address correspondence to: Rexford S. weight-reduced state was associated with investigation is whether obese individu- Ahima, University of Pennsylvania School increased activity in the brainstem, para- als with disproportionately low leptin of Medicine, Division of Endocrinology, hippocampal gyrus, culmen, and globus levels might benefit from leptin therapy. Diabetes, and Metabolism, 712A Clinical pallidus, as well as areas in the frontal and This strategy is akin to insulin treatment Research Building, 415 Curie Boulevard, temporal cortex involved in decision-mak- in patients with char- Philadelphia, Pennsylvania 19104, USA. ing functions. As predicted, leptin replace- acterized by relative insulin deficiency Phone: (215) 573-1872; Fax: (215) 573-5809; ment in the weight-reduced state reversed resulting from pancreatic β cell failure. E-mail: [email protected]. brain activity to the pattern observed at Population studies indicate that approxi- the initial weight. These findings could mately 10% of obese individuals have low 1. Ogden, C.L., Yanovski, S.Z., Carroll, M.D., and Fle- gal, K.M. 2007. The . Gastro- have been strengthened by the inclusion plasma leptin levels (6). Are these obese enterology. 132:2087–2102. of subjective ratings of appetite and mea- individuals truly leptin deficient? Does 2. Zhang, Y., et al. 1994. Positional cloning of the mouse surement of other circulating metabolic low leptin level portend obesity later on obese gene and its human homologue [erratum 1995, 374:479]. Nature. 372:425–432. factors aside from leptin. Furthermore, in life? Indeed, humans and rodents with 3. Morton, G.J., et al. 2006. Central nervous system BOLD signals do not establish whether heterozygous mutation of the gene encod- control of food intake and body weight. Nature. the brain regions affected by leptin are ing leptin manifest partial leptin defi- 443:289–295. 4. Rosenbaum, M., Sy, M., Pavlovich, K., Leibel, targeted directly or indirectly. ciency, increased body fat, and abnormal R.L., and Hirsch, J. 2008. Leptin reverses weight Nonetheless, the study extends the recent and lipid metabolism (18, 19). loss–induced changes in regional neural activ- mapping of brain responses in patients Reduced leptin levels may precede obesity ity responses to visual food stimuli. J. Clin. Invest. 118:2583–2591. with congenital leptin deficiency (15, and predict a poor outcome to weight loss 5. Ahima, R.S., et al. 1996. Role of leptin in the neuro- 16). Farooqi et al. determined that in the (20, 21). Thus, screening for partial leptin endocrine response to fasting. Nature. 382:250–252. leptin-deficient state, images of well-liked deficiency could identify obese individu- 6. Flier, J.S. 1998. Clinical review 94: what’s in a name? In food elicited a desire to eat even when the als in need of leptin replacement therapy. search of leptin’s physiologic role. J. Clin. Endocrinol. Metab. 83:1407–1413. subjects had just eaten (15). In contrast, Mapping of the structure, chemistry, and 7. Heymsfield, S.B., et al. 1999. Recombinant leptin after leptin treatment, images of well-liked electrical activity of the human brain may for weight loss in obese and lean adults: a ran- food elicited a desire to eat only during also offer insights into therapeutic strat- domized, controlled, dose-escalation trial. JAMA. 282:1568–1575. fasting (15). The latter was similar to nor- egies targeting the central processing of 8. Welt, C.K., et al. 2004. Recombinant human leptin mal subjects and related to leptin’s abil- food stimuli. in women with hypothalamic amenorrhea. N. Engl.

2382 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 7 July 2008 commentaries

J. Med. 351:987–997. tion on energy expenditure and circulating concen- 18. Farooqi, I.S., et al. 2001. Partial leptin deficiency 9. Chan, J.L., et al. 2003. The role of falling leptin trations of thyroid hormones. J. Clin. Endocrinol. and human adiposity. Nature. 414:34–35. levels in the neuroendocrine and metabolic adap- Metab. 87:2391–2394. 19. Begriche, K., et al. 2008. Partial leptin deficiency tation to short-term starvation in healthy men. 14. Rosenbaum, M., et al. 2005. Low-dose leptin revers- favors diet-induced obesity and related metabolic J. Clin. Invest. 111:1409–1421. es skeletal muscle, autonomic, and neuroendocrine disorders in mice. Am. J. Physiol. Endocrinol. Metab. 10. Farooqi, I.S., et al. 2002. Beneficial effects of leptin adaptations to maintenance of reduced weight. 294:E939–E951. on obesity, T cell hyporesponsiveness, and neuroen- J. Clin. Invest. 115:3579–3586. 20. Verdich, C., et al. 2001. Leptin levels are associated docrine/metabolic dysfunction of human congeni- 15. Farooqi, I.S., et al. 2007. Leptin regulates stria- with fat oxidation and dietary-induced weight loss tal leptin deficiency. J. Clin. Invest. 110:1093–1103. tal regions and human eating behavior. Science. in obesity. Obes. Res. 9:452–461. 11. Oral, E.A., et al. 2002. Leptin-replacement therapy 317:1355. 21. Filozof, C.M., et al. 2000. Low plasma leptin con- for lipodystrophy. N. Engl. J. Med. 346:570–578. 16. Baicy, K., et al. 2007. Leptin replacement alters centration and low rates of fat oxidation in weight- 12. Oral, E.A., et al. 2002. Effect of leptin replacement brain response to food cues in genetically leptin- stable post-obese subjects. Obes. Res. 8:205–210. on pituitary hormone regulation in patients with deficient adults. Proc. Natl. Acad. Sci. U. S. A. 22. Batterham, R.L., et al. 2007. PYY modulation of cor- severe lipodystrophy. J. Clin. Endocrinol. Metab. 104:18276–18279. tical and hypothalamic brain areas predicts feeding 87:3110–3117. 17. Boozer, C.N., et al. 2001. Synergy of sibutramine behaviour in humans. Nature. 450:106–109. 13. Rosenbaum, M., et al. 2002. Low dose leptin admin- and low-dose leptin in treatment of diet-induced 23. [No authors listed]. 2007. Gastroenterology. 132(Issue istration reverses effects of sustained weight-reduc- obesity in rats. Metabolism. 50:889–893. 6), cover figure. How irritating: the role of TRPA1 in sensing cigarette smoke and aerogenic oxidants in the airways Sidney A. Simon1 and Wolfgang Liedtke1,2

1Department of Neurobiology and 2Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, North Carolina, USA.

Airway irritants cause a variety of lung pathologies. Two separate studies, chemical irritants that activate PMNs the first recently reported in the JCI by Bessac et al. and the second reported include capsaicin (the pungent compound by Andrè et al. in the current issue of the JCI (see the related article begin- in chili pepper and Mace brand defense ning on page 2574), have identified irritants that activate transient receptor sprays), allyl isothiocyanate (present in potential cation channel, subfamily A, member 1 (TRPA1) receptors in air- mustard, wasabi, and horseradish), form- way sensory neurons, resulting in neurogenic inflammation and respiratory aldehyde, nicotine, acid, hydrogen perox- hypersensitivity. The identification of TRPA1 activation by toxicants from ide (H2O2), , acrolein, and, finally, cigarette smoke and polluted air, such as crotonaldehyde, acrolein, and oxi- smoke generated from tobacco. The latter dizing agents such as hydrogen peroxide, is an important finding. These two differs from the other compounds in that it studies enhance our understanding of how pollution and cigarette smoke comprises at least 5,000 distinct chemicals can damage airway function and will hopefully pave the way for the develop- at varying concentrations. ment of rational alternative therapeutics for such airway injury. Although there are many types of PMNs, the most common are those that are acti- Inhalation of pollutants is associated tification of their receptors on epithelial vated by capsaicin through its receptor, with adverse cardiovascular and respira- cells and on sensory neurons that inner- transient receptor potential cation channel, tory diseases and may lead to an increase vate these cells. subfamily V, member 1 (TRPV1). TRPV1 is in mortality. In addition, persons with a member of the TRPV subfamily of ion sensitized airways often display respira- Anatomy of airways and transient channels that are all inhibited by the poly- tory hypersensitivity to many chemical receptor potential channels valent cationic dye and ion channel blocker irritants found in polluted air. Two criti- The airways are innervated by branches of ruthenium red, but specific antagonists cal issues in understanding the etiology the trigeminal and vagal nerves (Figure 1). may exist for individual transient receptor of these pathologies are the identification Among the many classes of nerve fibers are potential channels. For TRPV1, one such of the responsible chemicals and the iden- the polymodal nociceptors (PMNs). These antagonist is capsazepine, a synthetic ana- unmyelinated neurons send signals that logue of capsaicin. When capsaicin-sensi- cause the perception of pain in response to tive neurons are activated, they transmit Nonstandard abbreviations used: CSE, cigarette potentially damaging thermal, mechani- nociceptive information to upstream relay smoke aqueous extract; DRG, dorsal root ganglia; TRPA1, transient receptor potential cation channel, cal, and chemical stimuli. Their activation centers within the CNS that are associated subfamily A, member 1; TRPV1, transient receptor induces protective reflexes and nocifensive with pain perception and, importantly, potential cation channel, subfamily V, member 1. behaviors (defensive behavior that is elicit- these neurons also release proinflammato- Conflict of interest: The authors receive financial ed by sensory stimuli that have the poten- ry mediators (1). With respect to cigarette support from Philip Morris USA and Philip Morris International. tial to cause injury) that include apnea, bra- smoke aqueous extract (CSE) as a stimu- Citation for this article: J. Clin. Invest. 118:2383–2386 dycardia, coughing, mucus secretion, and lus, capsaicin-sensitive nociceptors appear (2008). doi:10.1172/JCI36111. avoidance behavior. Some well established to have an important role in physiological

The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 7 July 2008 2383