| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SYMPOSIUM REPORT |
1 Neurology Service, VA Medical Center, East Orange, New Jersey and Department of Neurology and Neurosciences, New Jersey Medical School, Newark, NJ, USA
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
(Received 26 April 2007;
accepted after revision 18 June 2007;
first published online 21 June 2007)
Corresponding author B. E. Levin: Neurology Service (127C), VA Medical Center, 385 Tremont Avenue, E. Orange, NJ 07018–1095, USA. Email: levin{at}umdnj.edu
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
Homeostatic regulation of energy balance
To understand why some of us might be metabolically more suited to survive periods of intermittent food availability and why this might lead to obesity, we must first examine the regulatory mechanisms which drive us to eat. The discovery of leptin (Zhang et al. 1994) confirmed Kennedy's lipostatic hypothesis by which enlarging adipose depots produce a factor which is monitored by the brain as a negative feedback signal to inhibit further intake (Kennedy, 1953). Leptin, as well as insulin, is produced in direct proportion to the amount of adipose tissue (Woods & Seeley, 2002). There are also many other metabolic, hormonal and hard-wired neural signals which constantly inform the brain as to the metabolic status of the body. These signals are monitored both by peripheral sensors in the hepatic portal vein, small intestines and carotid body and by specialized ‘metabolic sensing’ neurons in the brain (Levin et al. 2004b). These neurons, unlike most others, utilize substrates such as glucose and fatty acids as signalling molecules to regulate their membrane potential and neural activity (Levin et al. 2004b). They also have receptors for leptin, insulin and other hormones and peptides which are transported into the brain across the blood–brain barrier (Levin et al. 2004b). Metabolic sensing neurons are organized in localized, interconnected sites which are widely distributed the brain. These sites include important neuroendocrine and autonomic centres in the brainstem and hypothalamus and reward areas of the mid- and forebrain (Levin et al. 2006). The efferents of this distributed network of sensors provide behavioural, neuroendocrine and autonomic outputs which ensure a homeostatic balance among ingestion, energy expenditure and storage. When this system is in true balance, body weight and adiposity remain stable over long periods of time.
First described as ‘glucosensing’ because they alter their activity in direct response to ambient glucose levels (Anand et al. 1964; Oomura et al. 1964), it is clear that these neurons also respond to leptin, insulin, ghrelin, fatty acids, ketone bodies and lactate, as well as intrinsic neurotransmitters and peptides (Routh et al. 1997; Spanswick et al. 2000; Cowley et al. 2003; Levin et al. 2004b; Song & Routh, 2005; Migrenne et al. 2006). Arcuate hypothalamic nucleus (ARC) neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons which release 
-melanocyte stimulating hormone (-MSH) are among the best characterized metabolic sensing neurons. They have synaptic interconnections with each other and overlapping projections to important neuroendocrine and autonomic efferent areas such as the paraventricular nucleus and lateral hypothalamic area (LHA) (Cowley, 2003; Bouret et al. 2004). Release of -MSH onto melanocortin 3 and 4 receptors at these targets produces a potent catabolic drive; food intake is inhibited, adipose and glycogen stores are depleted and energy expenditure is stimulated (Alessi et al. 1988; Haynes et al. 1998; Obici et al. 2001). Release of NPY provides a potent anabolic drive; food seeking and ingestion are stimulated and energy expenditure is inhibited (Clark et al. 1985; Billington et al. 1991). In addition, ARC NPY neurons release AgRP, which is a functional antagonist at melanocortin receptors (Ollmann et al. 1997). Both leptin and insulin inhibit NPY and AgRP and stimulate POMC production (Woods & Seeley, 2002). Similarly, glucose inhibits activity in NPY and stimulates POMC neuronal activity (Muroya et al. 1999; Ibrahim et al. 2003). Both of these neurons project onto LHA orexin (hypocretin) and melanin concentrating hormone (MCH) neurons (Broberger et al. 1998). These neurons in turn project widely throughout the brain and act as downstream mediators of a wide variety of behavioural, neuroendocrine and metabolic functions such as arousal, motor and autonomic activity, ingestion and reward required for the regulation of all aspects of energy homeostasis (Kokkotou et al. 2001; Levin, 2006).
Why do some of us get fat?
Obesity results when individuals ingest more energy than they expend resulting in fat storage in adipose depots. Although the most important roles for leptin and centrally acting insulin are often thought to be the limitation of excess intake and prevention of obesity, it is unlikely that these are primary roles of either. Obesity was rare in early hunter–gather and agrarian societies and is unusual among feral animals, presumably because the supply of food is cyclical or unpredictable (Diamond, 1997). Under such conditions, the ability to ingest and store as many calories as possible when food is readily available would have obvious survival value, especially in anticipation of the oncoming winter. But, to do so, the individual would have to minimize the impact of leptin and insulin as negative feedback signals as adipose stores enlarge. Thus, those individuals with a raised threshold for sensing and responding to such peripheral inhibitory signals would be best suited to enlarge their energy stores.
While there are no data in pre-obese human beings which support such a raised sensing threshold, this phenomenon has been demonstrated in rodents. There are individuals in some strains of outbred and selectively bred rats which are obesity prone and those that are obesity resistant when the fat and caloric content of their diets is raised (Hill et al. 1983; Levin et al. 1997). The obesity-prone rats have reduced leptin signalling in the ARC associated with attenuated anorectic and thermogenic responses to leptin (Levin & Dunn-Meynell, 2002c; Levin et al. 2004a; Gorski et al. 2007; Irani et al. 2007). They also have reduced ARC insulin signalling and a decreased anorectic response to centrally administered insulin (Clegg et al. 2005; Irani et al. 2007). In addition, their ability to sense and respond to glucose is reduced compared to obesity-resistant rats (Levin et al. 2004b). Importantly, all of these features are present before these rats become obese suggesting that they are genetically determined. Together, their reduced ability to respond to inhibitory signals from the periphery would allow such rats to eat beyond their metabolic needs on high fat, high calorie diets.
In fact, while obesity-resistant rats readily compensate for the increased caloric density of such diets, obesity-prone rats take almost 4 weeks to down-regulate their caloric intake despite an early, marked increase in plasma leptin levels (Levin & Dunn-Meynell, 2002c; Levin et al. 2003). By that time, their body weight and adipose set-points are irreversibly elevated and they avidly defend them against chronic caloric restriction (Levin & Keesey, 1998). A similar phenomenon occurs in many post-obese humans who, unless they markedly increase their energy expenditure by exercising, have a persistent reduction in resting energy expenditure and an apparently irresistible drive to regain lost weight (Leibel & Hirsch, 1984). It is important to point out that, while leptin resistance is a constant feature of already obese rodents (Van Heek et al. 1997; El-Haschimi et al. 2000; Madiehe et al. 2000) and humans (Schwartz et al. 1996; Rosenbaum et al. 2005), it is less clear that such reduced leptin responsiveness actually pre-dates the onset of obesity as it does in some obesity-prone rats.
Why can't I lose weight and keep it off?
No matter what the state of their adipose stores, both lean and obese individuals mount an identical set of defences when energy intake is restricted below their ongoing metabolic needs (Levin & Keesey, 1998; Levin & Dunn-Meynell, 2000). This otherwise protective set of responses is an important contributor to the inability of obese individuals to sustain weight loss over long periods of time. When obese individuals reduce their energy intake during dieting, sympathetic activity is increased to mobilize glucose from hepatic glycogen and fatty acids from adipose stores to provide an ongoing source of metabolic fuels (Beuers & Jungermann, 1990; Migliorini et al. 1997). Sympathetic activation in adipose tissue produces a marked drop in leptin production which far exceeds the loss of fat from these depots (Levin & Keesey, 1998; Ricci & Fried, 1999; Levin & Dunn-Meynell, 2000). Reduced leptin levels contribute to decreased muscle and other thermogenic organ sympathetic activity which causes decreased resting energy expenditure (Haynes et al. 1997; Rosenbaum et al. 1997; Minokoshi & Kahn, 2003). Leptin withdrawal also dysinhibits NPY/AgRP and inhibits POMC neurons causing a strong drive to seek and ingest food. In lean individuals, these processes are highly protective. However, in the weight-reduced obese, this strong drive is likely to be responsible for their 90% recidivism rate for weight regain (Leibel et al. 1995; Rosenbaum et al. 2002; MacLean et al. 2004).
In addition to these homeostatic processes, there are non-homeostatic systems which respond to the rewarding properties of food (e.g. palatability) and the positive psychosocial factors associated with meal taking. These are the same systems which participate in drug seeking behaviour (Berthoud, 2002) and they can drive even obesity-resistant individuals to eat far beyond the limits set by the homoeostatic systems in which leptin and insulin participate. Studies in rats support the contention that genetic predilection does not determine who will become obese on extremely rewarding diets, even those with low calorie and fat content (Keesey et al. 1978; Levin & Dunn-Meynell, 2002a). But even non-homeostatic systems follow some regulatory rules. The defended level of body weight reached on such diets has its own set-point which is totally dependent upon diet palatability. Thus, the extreme levels of obesity reached by both obesity-prone and obesity-resistant animals fed diets which are highly palatable but low in both calorie and fat content are not maintained once the palatability of the diet is reduced (Levin & Dunn-Meynell, 2002a). Therefore, while highly palatable diets can drive even the obesity-resistant to gain massive amounts of adiposity, obesity is sustained only in those with a genetic predisposition to become obese, and then only if the palatable diet also is high in fat and caloric density. The prediction from such studies would be that engagement of non-homeostatic pathways can cause obesity in those who are genetically programmed to be obesity resistant. However, these individuals also should be those most likely to be successful at losing and sustaining weight loss once non-homeostatic factors are minimized. On the other hand, in societies where fast-food chains provide supersized portions of low cost, highly palatable foods which are also calorically dense, obesity-prone individuals are the most susceptible to the double-barrelled assault on both their homeostatic and non-homeostatic defences of body weight.
The interaction of genetic predisposition and metabolic factors encountered during the perinatal period represents an additional way in which homeostatic controls can be overridden or pushed towards a higher set-point. In rats, maternal obesity during the perinatal period makes obesity-prone, but not obesity-resistant, offspring more obese as adults. However, obesity-resistant offspring do become obese when fostered postnatally with genetically obese dams (Levin & Govek, 1998; Reifsnyder et al. 2000; Levin & Dunn-Meynell, 2002b; Gorski & Levin, 2004; Levin et al. 2005). Thus, external environmental pressures of all sorts are important contributors to the development and maintenance of obesity, especially in genetically predisposed individuals.
Summary and conclusions: is there hope for the obese individual?
Short of bariatric surgery, which is often effective but carries the disadvantages associated with surgically altering the structure and function of the gastrointestinal tract (Klem et al. 2000), there are few good alternatives presently available to produce permanent weight loss. Currently there are no drugs which produce significant, sustained weight loss without unacceptable side-effects. While behavioural therapy is successful in some individuals (Lang & Froelicher, 2006), the time and expense required makes this mode of treatment impractical for many obese individuals. Intensive exercise has been used by many of the previously obese to sustain weight loss (Wing & Hill, 2001); but again, the level of activity required is beyond the ability of most individuals to sustain.
Given the overwhelming power of the homeostatic and non-homeostatic processes which oppose sustained weight loss in previously obese individuals, the best ‘treatment’ for obesity is prevention. Animal studies strongly suggest that such prevention will have to begin during the perinatal period and continue well into adolescence. It is during this developmental period that the neural pathways mediating the regulation of energy homeostasis can be most effectively altered by external manipulations. Such early interventions can have a positive impact on the development of these pathways to produce a permanent lowering of the defended body weight, even in obesity-prone individuals (Levin & Dunn-Meynell, 2002b; Bouret et al. 2004). However, continued research will be required to gain a better understanding of the mechanisms by which such a sustain effect can be achieved to stem the tide of the rapidly evolving obesity epidemic.
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
-MSH in the hypothalamus and caudal medulla. Peptides 9, 689–695.[CrossRef][Medline]Anand BK, Chhina GS, Sharma KN, Dua S & Singh B (1964). Activity of single neurons in the hypothalamus feeding centers: effect of glucose. Am J Physiol 207, 1146–1154.
Berthoud HR (2002). Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev 26, 393–428.[CrossRef][Medline]
Beuers U & Jungermann K (1990). Relative contribution of glycogenolysis and gluconeogenesis to basal, glucagon- and nerve stimulation-dependent glucose output in the perfused liver from fed and fasted rats. Biochem Int 21, 405–415.[Medline]
Billington CJ, Briggs JE, Grace M & Levine AS (1991). Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. Am J Physiol Regul Integr Comp Physiol 260, R321–R327.
Bouret SG, Draper SJ & Simerly RB (2004). Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 24, 2797–2805.
Broberger C, De Lecea L, Sutcliffe JG & Hokfelt T (1998). Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 402, 460–474.[CrossRef][Medline]
Clark JT, Kalra PS & Kalra SP (1985). Neuropeptide Y stimulates feeding but inhibits sexual behavior in rats. Endocrinology 117, 2435–2442.[Abstract]
Clegg DJ, Benoit SC, Reed JA, Woods SC & Levin BE (2005). Reduced anorexic effects of insulin in obesity-prone rats and rats fed a moderate fat diet. Am J Physiol Regul Integr Comp Physiol 288, R981–R986.
Corbett SW, Stern JS & Keesey RE (1986). Energy expenditure in rats with diet-induced obesity. Am J Clin Nutr 44, 173–180.
Cowley MA (2003). Hypothalamic melanocortin neurons integrate signals of energy state. Eur J Pharmacol 480, 3–11.[CrossRef][Medline]
Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD & Horvath TL (2003). The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661.[CrossRef][Medline]
Diamond J (1997). Guns, Germs and Steel. W.W. Norton, New York, London.
El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C & Flier JS (2000). Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105, 1827–1832.[Medline]
Gorski JN, Dunn-Meynell AA & Levin BE (2007). Maternal obesity increases hypothalamic leptin receptor expression and sensitivity in juvenile obesity-prone rats. Am J Physiol Regul Integr Comp Physiol 292, R1782–R1791.
Gorski J & Levin BE (2004). Effects of cross fostering on body weight, adiposity and insulin sensitivity in selectively bred obesity-prone and resistant rats. Obes Res 12, A103.
Haynes WG, Morgan DA, Djalali A & Mark AL (1998). Activation of melanocortin-4 receptors enhances thermogenic sympathetic nerve activity to brown adipose tissue. Hypertension 32, 620A.
Haynes WG, Sivitz WI, Morgan DA, Walsh SA & Mark AL (1997). Sympathetic and cardiorenal actions of leptin. Hypertension 30, 619–623.
Hill JO, Fried SK & Digirolamo M (1983). Effects of a high-fat diet on energy intake and expenditure in rats. Life Sci 33, 141–149.[Medline]
Ibrahim N, Bosch MA, Smart JL, Qiu J, Rubinstein M, Ronnekleiv OK, Low MJ & Kelly MJ (2003). Hypothalamic proopiomelanocortin neurons are glucose responsive and express KATP channels. Endocrinol 144, 1331–1340.
Irani BG, Dunn-Meynell AA & Levin BE (2007). Altered hypothalamic leptin, insulin and melanocortin binding associated with moderate fat diet and predisposition to obesity. Endocrinology 148, 310–316.
Keesey RE, Boyle PC & Storlien LH (1978). Food intake and utilization in lateral hypothalamically lesioned rats. Physiol Behav 21, 265–268.[CrossRef][Medline]
Kennedy GC (1953). The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci 611, 221–235.
Klem ML, Wing RR, Chang CC, Lang W, McGuire MT, Sugerman HJ, Hutchison SL, Makovich AL & Hill JO (2000). A case-control study of successful maintenance of a substantial weight loss: individuals who lost weight through surgery versus those who lost weight through non-surgical means. Internat J Obes Relat Metab Disord 24, 573–579.[CrossRef]
Kokkotou EG, Tritos NA, Mastaitis JW, Slieker L & Maratos-Flier E (2001). Melanin-concentrating hormone receptor is a target of leptin action in the mouse brain. Endocrinol 142, 680–686.
Lang A & Froelicher ES (2006). Management of overweight and obesity in adults: behavioral intervention for long-term weight loss and maintenance. Eur J Cardiovasc Nurs 5, 102–114.[CrossRef][Medline]
Leibel RL & Hirsch J (1984). Diminished energy requirements in reduced-obese patients. Metabolism 33, 164–170.[CrossRef][Medline]
Leibel RL, Rosenbaum M & Hirsch J (1995). Changes in energy expenditure resulting from altered body weight. N Engl J Med 332, 621–628.
Levin BE (2006). Orexins: neuropeptides for all seasons and functions. Am J Physiol Regul Integr Comp Physiol 291, R885–R888.
Levin BE & Dunn-Meynell AA (2000). Defense of body weight against chronic caloric restriction in obesity-prone and -resistant rats. Am J Physiol Regul Integr Comp Physiol 278, R231–R237.
Levin BE & Dunn-Meynell AA (2002a). Defense of body weight depends on dietary composition and palatability in rats with diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 282, R46–R54.
Levin BE & Dunn-Meynell AA (2002b). Maternal obesity alters adiposity and monoamine function in genetically predisposed offspring. Am J Physiol Regul Integr Comp Physiol 283, R1087–R1093.
Levin BE & Dunn-Meynell AA (2002c). Reduced central leptin sensitivity in rats with diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 283, R941–R948.
Levin BE, Dunn-Meynell AA, Balkan B & Keesey RE (1997). Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol 273, R725–R730.
Levin BE, Dunn-Meynell AA & Banks WA (2004a). Obesity-prone rats have normal blood–brain barrier transport but defective central leptin signaling prior to obesity onset. Am J Physiol Regul Integr Comp Physiol 286, R143–R150.
Levin BE, Dunn-Meynell AA, Ricci MR & Cummings DE (2003). Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats. Am J Physiol Endocrinol Metab 285, E949–E957.
Levin BE & Govek E (1998). Gestational obesity accentuates obesity in obesity-prone progeny. Am J Physiol Regul Integr Comp Physiol 275, R1374–R1379.
Levin BE, Kang L, Sanders NM & Dunn-Meynell AA (2006). Role of neuronal glucosensing in the regulation of energy homeostasis. Diabetes 55 (Suppl. 2), S122–S130.
Levin BE & Keesey RE (1998). Defense of differing body weight set-points in diet-induced obese and resistant rats. Am J Physiol Regul Integr Comp Physiol 274, R412–R419.
Levin BE, Magnan C, Migrenne S, Chua SC Jr & Dunn-Meynell AA (2005). The F-DIO obesity-prone rat is insulin resistant prior to obesity onset. Am J Physiol Regul Integr Comp Physiol 289, R704–R711.
Levin BE, Routh VH, Kang L, Sanders NM & Dunn-Meynell AA (2004b). Neuronal glucosensing: What do we know after 50 years? Diabetes 53, 2521–2528.
MacLean PS, Higgins JA, Johnson GC, Fleming-Elder BK, Peters JC & Hill JO (2004). Metabolic adjustments with the development, treatment, and recurrence of obesity in obesity-prone rats. Am J Physiol Regul Integr Comp Physiol 287, R288–R297.
Madiehe AM, Schaffhauser AO, Braymer DH, Bray GA & York DA (2000). Differential expression of leptin receptor in high- and low-fat-fed Osborne-Mendel and S5B/Pl rats. Obes Res 8, 467–474.[Medline]
Migliorini RH, Garofalo MA & Kettelhut IC (1997). Increased sympathetic activity in rat white adipose tissue during prolonged fasting. Am J Physiol Regul Integr Comp Physiol 272, R656–R661.
Migrenne S, Cruciani-Guglielmacci C, Kang L, Wang R, Rouch C, Lefevre AL, Ktorza A, Routh VH, Levin BE & Magnan C (2006). Fatty Acid signaling in the hypothalamus and the neural control of insulin secretion. Diabetes 55 (Suppl. 2), S139–S144.
Minokoshi Y & Kahn BB (2003). Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle. Biochem Soc Trans 31, 196–201.[Medline]
Muroya S, Yada T, Shioda S & Takigawa M (1999). Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neurosci Lett 264, 113–116.[CrossRef][Medline]
Obici S, Feng Z, Tan J, Liu L, Karkanias G & Rossetti L (2001). Central melanocortin receptors regulate insulin action. J Clin Invest 108, 1079–1085.[CrossRef][Medline]
Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I & Barsh GS (1997). Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138.
Oomura Y, Kimura K, Ooyama H, Maeo T, Iki M & Kuniyoshi N (1964). Reciprocal activities of the ventromedial and lateral hypothalamic area of cats. Science 143, 484–485.
Reifsnyder PC, Churchill G & Leiter EH (2000). Maternal environment and genotype interact to establish diabesity in mice. Genome Res 10, 1568–1578.
Ricci MR & Fried SK (1999). Isoproterenol decreases leptin expression in adipose tissue of obese humans. Obes Res 7, 233–240.[Medline]
Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E & Leibel RL (2005). Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 115, 3579–3586.[CrossRef][Medline]
Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE & Leibel RL (2002). Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab 87, 2391–2394.
Rosenbaum M, Nicolson M, Hirsch J, Murphy E, Chu F & Leibel RL (1997). Effects of weight change on plasma leptin concentrations and energy expenditure. J Clin Endocrinol Metab 82, 3647–3654.
Routh VH, McArdle JJ, Spanswick DC, Levin BE & Ashford MLJ (1997). Insulin modulates the activity of glucose responsive neurons in the ventromedial hypothalamic nucleus (VMN). Abs Soc Neurosci 23, 577A.
Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte J & D (1996). Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans. Nature Med 2, 589–593.[CrossRef][Medline]
Song Z & Routh VH (2005). Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54, 15–22.
Spanswick D, Smith MA, Mirshamsi S, Routh VH & Ashford ML (2000). Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3, 757–758.[CrossRef][Medline]
Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD & Davis HR Jr (1997). Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest 99, 385–390.[Medline]
Wing RR & Hill JO (2001). Successful weight loss maintenance. Ann Rev Nutr 21, 323–341.[CrossRef][Medline]
Woods SC & Seeley RJ (2002). Understanding the physiology of obesity: review of recent developments in obesity research. Int J Obes Relat Metab Disord 26 (Suppl. 4), S8–S10.[CrossRef]
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.
This article has been cited by other articles:
|
|
 |
|
  S. Chearskul, E. Delbridge, A. Shulkes, J. Proietto, and A. Kriketos Effect of weight loss and ketosis on postprandial cholecystokinin and free fatty acid concentrations Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1238 - 1246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Mifflin and A. Strack Obesity and the central nervous system J. Physiol., September 1, 2007; 583(2): 423 - 423. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
