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Department of Medicine (M.W.S.), Harborview Medical Center and University of Washington, Seattle, Washington, 98104; and Department of Medicine (K.D.N.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6303
Address all correspondence and requests for reprints to: Prof. Michael Schwartz, Department of Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359757, Seattle, Washington 98104. E-mail: mschwart{at}u.washington.edu; or Kevin Niswender, Diabetes, Endocrinology and Metabolism, 715 Preston Research Building, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, Tennessee 37232-6303. E-mail: kevin.niswender{at}vanderbilt.edu.
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Abstract |
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 Top Abstract IntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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Introduction |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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A second key question stemming from this hypothesis that has yet to be answered is how obesity can be so common if fat mass is subject to homeostatic regulation. How do we explain the glaring disconnect between the unchallengeable conclusions from rodent studies and the rapidly growing obesity epidemic? Given the emergence of obesity as a leading public health problem (7) and the fact that, with the exception of certain bariatric surgical procedures (8), obesity treatment has improved little over the years and remains largely ineffective (9), answers to these questions are desperately needed.
Some have argued that the biological system controlling energy homeostasis evolved principally to protect against weight loss rather than weight gain (10, 11, 12). From the perspective of this Absence of Protection model, the current obesity epidemic is seen as an inevitable consequence of exposing a defenseless populace to an ever more obesigenic environment. An alternative hypothesis, referred to here as the Central Resistance model, is that the biological defense of body energy stores is capable of protecting against pathological weight gain but that genetic and/or acquired resistance to adiposity-regulating hormones occurs commonly and undermines this biological protection (13, 14). It is both surprising and disconcerting that, for all of our recent progress, we still don’t know whether obesity is a natural consequence of modern society or the manifestation of a biochemical disorder of energy homeostasis. In this perspective, we highlight issues at the heart of this controversy and suggest a strategy for distinguishing between these two views of obesity pathogenesis.
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Energy Homeostasis and the Thrifty Genotype Hypothesis |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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A great strength of this hypothesis is its ability to place the origin of the current obesity epidemic in evolutionary terms, such that once-adaptive gene variants are implicated in pathological weight gain when they are expressed by individuals living in an obesigenic environment (e.g. one that is characterized by ready availability of highly palatable, energy-rich foods and by minimal demand for physical activity).
Of central importance to both the thrifty genotype hypothesis and the biology of energy homeostasis (whether defending against weight loss or weight gain) is the concept that changes of body energy stored in the form of fat are communicated to the central nervous system (CNS) via afferent negative feedback signals. Such signals circulate in proportion both to body fat content and to recent changes in energy balance (5, 6); and, among a variety of proposed food-intake regulatory signals, leptin and insulin have emerged as the best candidates to serve this adiposity signaling role. Both hormones act in the brain to reduce food intake, increase energy expenditure, and lower body weight in a dose-dependent manner. These effects involve activation of the leptin and insulin receptors in key brain areas such as the hypothalamic arcuate nucleus, where neuronal subsets that respond to changes in ambient insulin and leptin levels have been identified (5, 6). Conversely, deficient neuronal signaling by either hormone leads to hyperphagia and weight gain, implying that both hormones play a physiological role to limit energy intake and storage in the body. Despite their divergent actions in other tissues (17), growing evidence suggests that the brain relies upon input from both hormones in the control of energy homeostasis (Fig. 1
) and, further, that extensive overlap exists in the cellular mechanisms mediating the actions of these hormones in the hypothalamus.
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Biological Basis for the Absence of Protection Model |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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One appealing aspect of this explanation for an inherent lack of defense against weight gain (due to the inability to recognize increasing plasma leptin levels as a biological signal) is its ready integration into the thrifty genotype hypothesis. This hypothesis predicts that if inadequate food availability (rather than too much food) was a major threat to survival over the course of human evolution, those individuals most capable of consuming and storing energy when food was available would be most likely to enjoy reproductive success; at the same time, the opportunity to become obese is presumed to have been so uncommon as to have little or no adverse impact on survival or reproductive success at the population level. Hence, inherent biological defense against weight gain, such as that conveyed by an elevated plasma leptin level, was not selected for (or was selected against) and remains undeveloped, whereas the defense against weight loss was strongly selected for and is much more robust.
The especially rapid and pervasive weight gain characteristic of many populations that immigrate to the US from more austere environs can be taken as evidence in support of this version of the Absence of Protection model, as is the disappointing response to leptin as a therapeutic agent in human subjects with common forms of obesity (18). In sum, the Absence of Protection model proposes that both the high prevalence of obesity and the limited efficacy of leptin as an obesity treatment modality are consequences of an inherent lack of biological protection against excessive weight gain (10, 11).
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Predictions from the Central Resistance Model |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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What would be the predicted consequence of biochemical resistance to neuronal input from insulin and leptin? If the brain perceives a reduced level of fat mass (due to reduced input from adiposity signals), neuronal pathways that promote increased food intake and reduced energy expenditure are predicted to be activated, leading to a state of positive energy balance and increased fat storage. This, in turn, will increase circulating levels of insulin and leptin, yielding a new steady-state in which normal levels of food intake are maintained in the face of elevated levels plasma insulin and leptin and of body fat mass. This pattern, of course, is characteristic of common forms of human obesity. According to this view, therefore, both common forms of obesity and the failure of leptin as a therapeutic agent are due to biochemical resistance, rather than to an inherent absence of neuronal systems capable of responding to signals generated by pathological expansion of body fat mass.
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Distinguishing between Models |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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That being said, the Absence of Protection model provides no ready explanation for the observation that some individuals are predisposed to obesity whereas others are not, even when they live in the same environment. Via what mechanism do genetic factors influence susceptibility to obesity if not by modifying the function of systems that defend against weight gain? Further, available data suggest that most obese individuals defend their body fat mass as robustly as do normal-weight individuals (19, 20, 21, 22). How does the Absence of Protection model account for the defense of an elevated level of body fat mass? These questions reveal fundamental weaknesses in the Absence of Protection model that justify careful scrutiny of the alternatives. For the Central Resistance model, this effort begins with a discussion of mechanisms underlying adiposity negative feedback.
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Leptin and Insulin Signal Transduction |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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Overlap also appears to exist in the mechanisms responsible for termination of signaling via receptors for insulin and leptin. As depicted in Fig. 2, protein tyrosine phosphatase-1B (PTP-1B) is an enzyme implicated in the termination of both leptin and insulin signal transduction by enzymatic cleavage of phosphate from key tyrosine residues of molecules in the signaling cascade (e.g. insulin receptor, IRS, JAK-2). Interestingly, PTP-1B knockout mice have increased sensitivity to both leptin and insulin (38, 39), suggesting a physiological role for this enzyme to limit signal transduction by both hormones.
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). For example, SOCS3 binds to phosphotyrosine residues on the insulin receptor and potently inhibits insulin-mediated tyrosine phosphorylation of IRS proteins (44) while also hastening ubiquitin-mediated degradation of IRS proteins (45). Consequently, overexpression of SOCS3 in liver is sufficient to cause marked insulin resistance and steatosis in mice (46). Importantly, recent data indicate that mice with SOCS3 haploinsufficiency or with neuron-specific SOCS3 deletion are resistant to diet-induced obesity (DIO) and have increased sensitivity to both leptin and insulin (47, 48). This phenotype is very similar to that induced by deletion of PTP-1B (29, 30).
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Criteria for Testing the Central Resistance Model |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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A mechanism should exist to explain how biochemical signal transduction activated by adiposity negative feedback signals is impaired by factors that predispose to obesity (e.g. consumption of a highly palatable, high-fat diet)
One appealing aspect of the aforementioned concept of shared insulin and leptin signal transduction mechanisms is the possibility that a single biochemical defect or set of interrelated defects can impair the response to both hormones. In this context, lessons learned from the study of insulin resistance in peripheral tissues are instructive. Growing evidence suggests that insulin action in peripheral tissues, such as skeletal muscle, is dependent upon activation of the IRS-PI3K pathway, and that impaired activation of this pathway plays a major role in the pathogenesis of insulin resistance associated with obesity and type 2 diabetes (49). One may therefore entertain the possibility that, in key neurons, impaired signaling via IRS-PI3K might contribute to central resistance to both insulin and leptin (23, 30, 50).
Several biochemical mechanisms have been forwarded to explain how obesity and nutrient excess might impair cell signaling via the IRS-PI3K pathway. One proposes that nutrient excess, especially when comprised of a mix of carbohydrate and fat, activates responses that protect cells from further insulin-stimulated nutrient influx (49, 50). According to one version of this model, a sustained increase in the level of fatty acyl coenzyme A in the intracellular compartment is proposed to signal nutrient excess and to initiate a cascade of events that dampen further insulin signal transduction (49, 50). Among these responses to cellular nutrient excess is the activation of cytokine-related intracellular signal transduction pathways that ultimately phosphorylate the insulin receptor and IRS proteins on serine residues, thereby reducing their inherent capacity to activate PI3K. Alternatively, cytokines elaborated systemically in response to excessive fat deposition may activate analogous cellular responses in insulin-sensitive tissues and thereby down-regulate signaling via IRS-PI3K. First shown for TNF
, this mechanism is of increasing interest, in light of growing evidence that obesity is a state of heightened macrophage activation and systemic cytokine production (51). Whether either or both of these mechanisms are activated in the hypothalamus of obese individuals is unknown at present, but both constitute plausible biochemical mechanisms by which resistance may occur.
Biochemical signal transduction and behavioral responses activated by adiposity negative feedback signals should be attenuated in common (i.e. diet-induced) obesity
Several studies have demonstrated that, in rodents, DIO impairs the anorexic response to centrally administered insulin or leptin (52, 53, 54), whereas the food-intake lowering response to these hormones is preserved in control animals fed a standard chow diet. Combined with compelling evidence that susceptibility to DIO is genetically determined (44), these results suggest that, in the appropriate environmental context, genetic factors can attenuate the capacity to perceive and respond to adiposity negative feedback signals. Additionally, it is clear that once DIO is established, the ability of leptin to activate hypothalamic STAT3 signaling is diminished (13, 55). Whether other biochemical responses to hypothalamic input from insulin and leptin (e.g. IRS-PI3K signaling) are similarly attenuated by DIO has yet to be determined.
Attenuation of the CNS response to adiposity signals should develop over a time course consistent with a causal role in either the development or maintenance of obesity
To date, studies have failed to clarify whether obesity-induced defects in leptin signal transduction are a cause or a consequence of obesity. The effect of DIO to attenuate leptin-induced activation of hypothalamic STAT3 signaling, for example, does not occur during the early phase of weight gain and was only documented after obesity was well established (48). By comparison, the effect of a highly palatable, high-fat diet to impair metabolic responses to systemically administered insulin and leptin occurs within 3 d of the change in diet (56). Further investigation is therefore needed to establish the time course over which behavioral, metabolic, and biochemical defects in the central response to insulin and leptin evolve when animals are placed on an obesigenic diet and the relationship of these responses to changes of body fat mass. Also of importance are studies to determine whether genetic variation in DIO susceptibility is related to the extent to which such diets compromise the CNS response to adiposity signals.
Although it is possible that a primary defect in hypothalamic signaling by insulin and leptin mediates the effect of a high-fat diet to increase food intake and body adipose mass in susceptible individuals, we note that any circumstance in which signaling by these hormones is dampened in key neurons could have deleterious consequences. Thus, even if other nonhypothalamic factors [i.e. diet palatability, reward (12)] drive the initial accumulation of body fat mass, hypothalamic resistance to leptin and insulin could favor the defense of the new, elevated level of adiposity. This consideration gives rise to a fourth criterion to be met by advocates of the Central Resistance model.
Preventing neuronal resistance to insulin and leptin should protect against common obesity (i.e. acquisition of resistance should be necessary for this type of obesity)
Although DIO impairs leptin-mediated STAT3 activation (46, 47, 48), and whereas interventions that reduce hypothalamic signal transduction via STAT3 are clearly sufficient to cause obesity (57), the fundamental question of whether maintenance of intact neuronal STAT3 signaling is sufficient to protect against obesity has not been tested directly. Similarly, little is known about whether DIO impairs hypothalamic signal transduction via IRS-PI3K, whether reduced hypothalamic PI3K signaling causes obesity, or whether maintenance of intact PI3K signaling in key neuronal subsets might protect against DIO.
Although much work therefore remains to be done, another approach to this key issue is to ask whether molecules that function to terminate signaling by insulin and leptin are necessary for DIO to occur. In this context, the phenotype of mice lacking PTP-1B, which can terminate signaling by both insulin and leptin receptors, is of compelling interest. Thus, PTP-1B deficiency not only increases sensitivity to both hormones but confers robust protection against DIO (58, 59), suggesting that signaling by molecules that dampen adiposity-related negative feedback may be required for this form of obesity to occur. Recent reports document a similar role for neuronal SOCS3 signaling: both SOCS3 haploinsufficiency and neuron-specific deletion of this protein confer protection against DIO and its metabolic sequelae (47, 48).
Taken together, these findings suggest that the pathogenesis of DIO is critically dependent upon PTP1-B and SOCS3, molecules that function to limit the intracellular response to input from insulin and leptin. This concept is made all the more interesting by the observation that many cytokines are capable of inducing SOCS3. If, as alluded to earlier, obesity-associated macrophage induction increases systemic cytokine levels, the resultant inflammatory milieu could potentially reduce signaling via both JAK-STAT (due to SOCS3 induction) and IRS-PI3K (due to serine phosphorylation of IRS proteins) pathways, thereby limiting neuronal signal transduction by both insulin and leptin.
Impaired leptin or insulin signal transduction in key neurons should be sufficient to induce obesity
Genetic deficiency of either leptin or its receptor induces severe hyperphagia and obesity in rodents and humans (4, 60, 61, 62). Thus, adaptive responses favoring weight gain are clearly activated when input from adiposity-negative feedback signals is reduced. That human obesity results from heterozygous inheritance of a mutant leptin allele (63) suggests further that even a modest reduction in leptin level (per unit fat mass) is sufficient to raise the defended level of body fat content. Reduced leptin signaling in the brain appears to explain this adaptive response, because neuron-specific deletion of leptin receptors in mice recapitulates the obesity phenotype seen with global leptin receptor deficiency (64).
This body of work was recently extended by a study in which leptin receptors were selectively deleted from cells that express proopiomelanocortin (POMC), the melanocortin precursor protein (65). The rationale underlying this study derives from ample evidence that the melanocortin system is a key hypothalamic mediator of anorexia induced by leptin (5). Consistent with this hypothesis, deletion of leptin receptors from POMC neurons caused obesity, although, as might have been expected, the disturbance of energy homeostasis was modest in comparison with animals that lack all leptin receptor protein. Neuron-specific insulin receptor knockout also causes an obesity syndrome in mice (66); again, this obesity syndrome is less pronounced than that seen in mice that lack leptin signaling. Importantly, interventions that reduce neuronal signaling via either STAT3 (36, 57) or IRS-2 (67, 68) also cause hyperphagia and obesity. These findings emphasize that, like insulin, leptin, and their receptors, adiposity-related signal transduction via both the JAK-STAT and IRS-PI3K mechanisms are also essential for normal energy homeostasis.
Thus, these observations collectively constitute strong evidence that signaling via leptin, insulin, JAK-STAT, and IRS-PI3K is required for intact defense against obesity and, by extension, that physiological systems for the defense against pathological weight loss are present in normal individuals. However, they are of limited value in the effort to distinguish between the Absence of Protection and Central Resistance models, because both models are founded on the premise that reduced input from adiposity-related signals activates responses that favor weight gain.
Protection should exist against weight gain induced independently of the voluntary consumption of a highly palatable diet
Involuntary overfeeding is an approach that has been used successfully to identify and characterize homeostatic responses that protect against pathological expansion of body fat mass. In animal models, this can be accomplished by infusing nutrients directly into the stomach. In both rodents (69) and nonhuman primates (70), this intervention induces pathological weight gain, but unlike DIO, spontaneous food intake decreases dramatically in this setting. Consequently, excess body weight arising from this type of overfeeding is fully dissipated in the days and weeks after the nutrient infusion is discontinued. Thus, weight gain during involuntary overfeeding is achieved despite activation of homeostatic responses that reduce caloric intake; once the infusion of calories into the gut is discontinued, this homeostatic response promotes the return to preintervention body weight.
A similar set of outcomes was observed in humans that participated in overfeeding studies. Keys and colleagues (71, 72) were the first to perform these studies. They observed that, of 20 male psychiatric inpatients that were encouraged to overeat from a selection of palatable foods, weight increased over a broad range (2.5–22.2 kg) during 6 months of the experiment. Important for this discussion is the observation that of the nine subjects that had gained the most weight (more that 10 kg), six proceeded to lose more than 10 kg over the next 18-months (72). Similarly, those that gained less weight during the study period tended to lose weight subsequently, but this weight loss was far less dramatic than in those that had gained a larger amount. The capacity to dissipate excess calories, therefore, seems to be inherent and can cause substantial weight loss when a transient stimulus to overeat is removed.
Subsequently, the Experimental Obesity in Man studies (20, 21, 22) characterized responses induced by paying subjects to consume approximately 3-fold more than their normal daily intake of calories over a period of several months. In the majority of subjects, the period of overfeeding (which can be considered involuntary, in the sense that subjects were motivated cognitively to overcome homeostatic responses that prevent weight gain) was followed by a sustained and dramatic reduction of food intake that resulted in a return to the baseline, preintervention body weight.
Additionally, unlike typical human obese subjects, individuals in these overfeeding studies consumed significantly more than the predicted number of calories to maintain their excess weight, suggesting the activation of a homeostatic response (i.e. an increase of energy expenditure) not observed in typical obesity. Indeed, Leibel et al. (19) demonstrated that maintenance of body weight at a level 10% above the usual weight was associated with an increase in total energy expenditure, demonstrating the inherent potential for counterregulation against nutrient excess (comprised of both reduced spontaneous food intake and increased metabolic rate) when it arises independently of the voluntary consumption of a preferred diet, a response implicated in the defense against obesity. Further, the observation that these responses are intact among already-obese individuals that are induced to maintain a further 10% increase of body weight (19) suggests that common forms of obesity are characterized by the homeostatic defense of an elevated level of body fat content, rather than by the absence of inherent defense against further weight gain.
Studies in rats have identified a hypothalamic mechanism involved in the homeostatic response to involuntary overfeeding. Seeley and colleagues (73), in collaboration with our group, investigated whether overfeeding stimulates hypothalamic POMC neurons and, if so, whether increased melanocortin signaling is required for protection against weight gain during involuntary overfeeding. As predicted, rats overfed via intragastric infusion of a high-energy nutrient solution exhibited a potent inhibition of spontaneous food ingestion, an effect that was associated with a robust increase of hypothalamic expression of mRNA for POMC. Furthermore, overfeeding-induced anorexia was fully blocked by central administration of a melanocortin receptor antagonist at a dose that had no effect on the intake of rats that were not overfed (73). The homeostatic response to involuntary overfeeding, therefore, involves activation of the melanocortin system, a key hypothalamic mediator of the response to adiposity signals.
The homeostatic response to involuntary overfeeding can be taken as indirect evidence against the Absence of Protection model, because it demonstrates that potent defense against excessive energy storage clearly exists, at least when the challenge is involuntary. This conclusion leads to an important question: What mechanism(s) can be invoked to explain the fundamental absence of this homeostatic response in rodent models of DIO, where the challenge is ad libitum, voluntary consumption of a highly palatable, energy-rich diet? In this context, we emphasize the observation that sensitivity to DIO is strongly determined by genetic factors, such that, whereas some mouse and rat strains are fully resistant to DIO (like some human populations), others are quite susceptible (74). It will be interesting in future studies to determine whether neuronal leptin and insulin resistance develops differently in the brain of animals that are overfed via voluntary consumption of a highly palatable diet than in those subjected to involuntary overfeeding.
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Concluding Remarks |
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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Acknowledgments |
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Footnotes |
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Abbreviations: CNS, Central nervous system; DIO, diet-induced obesity; IRS, insulin receptor substrate; JAK, Janus kinase; PI3K, phosphatidylinositol 3-OH kinase; POMC, proopiomelanocortin; PTP-1B, protein tyrosine phosphatase-1B; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription.
Received May 13, 2004.
Accepted August 31, 2004.
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TopAbstractIntroductionEnergy Homeostasis and the...Biological Basis for the...Predictions from the Central...Distinguishing between ModelsLeptin and Insulin Signal...Criteria for Testing the...Concluding RemarksReferences |
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