The Hormonal Control of Food Intake

Numerous circulating peptides and steroids produced in the body influence appetite through their actions on the hypothalamus, the brain stem, and the autonomic nervous system. These hormones come from three major sites—fat cells, the gastrointestinal tract, and the pancreas. In this Review we provide a synthesis of recent evidence concerning the actions of these hormones on food intake. Numerous circulating peptides and steroids produced in the body influence appetite through their actions on the hypothalamus, the brain stem, and the autonomic nervous system. These hormones come from three major sites—fat cells, the gastrointestinal tract, and the pancreas. In this Review we provide a synthesis of recent evidence concerning the actions of these hormones on food intake. Despite marked day-to-day fluctuations in food intake and physical activity, most healthy adult mammals maintain a steady body weight over many years. This indicates that cumulative energy intake is normally matched with great precision to energy expenditure. It has long been proposed that homeostatic regulators control energy balance. In the mid 20th century, Gordon Kennedy was the first to propose that circulating signals generated in proportion to body fat stores influenced food intake and energy expenditure in a coordinated manner to regulate body weight (Kennedy, 1953Kennedy G.C. The role of depot fat in the hypothalamic control of food intake in the rat.Proc. R. Soc. Lond. B. Biol. Sci. 1953; 140: 578-596Crossref PubMed Google Scholar). A series of contemporaneous experiments in which regions of the hypothalamus were physically ablated in rats showed that the hypothalamus was critical in this regulation (King, 2006King B.M. The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight.Physiol. Behav. 2006; 87: 221-244Crossref PubMed Scopus (361) Google Scholar). For example, damage to the ventromedial hypothalamus caused hyperphagia (eating in excess) and obesity whereas destruction of the lateral hypothalamus resulted in profound anorexia and weight loss. It was shown that circulating substances were capable of regulating food intake in parabiosis experiments (the surgical union of two animals allowing exchange of blood). Rats with lesions to the ventromedial hypothalamus parabiosed to normal animals remained hyperphagic and obese whereas the parabiosed partner ate less and lost weight. These experiments were the first to provide substantive evidence that a blood-borne satiety factor that was produced in obese animals required an intact hypothalamus for its activity. Despite the robustness of these physiological observations it took more than 40 years before the molecules involved in such homeostatic control were identified. In the past decade the body of knowledge has grown rapidly and has resulted in a sea change in our understanding of the physiological processes that control food intake. We now know that a number of circulating peptides and steroids that are produced in the body can have a substantial influence on appetitive behavior through their actions on the hypothalamus, the brain stem, or afferent autonomic nerves. These hormones come from at least three sites: fat cells, the gastrointestinal tract, and the endocrine pancreas. Progress toward identifying a circulating compound regulating satiation came from studying two naturally occurring obese mouse models, obese (ob/ob) and diabetic (db/db). Parabiosis experiments revealed ob/ob mice were deficient in a circulating satiety factor, whereas db/db mice produced the factor in excess but lacked the ability to respond to it (see Friedman and Halaas, 1998Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4541) Google Scholar). ob/ob mice were shown to harbor a loss-of-function mutation in the gene encoding a secreted peptide, named leptin, that is produced largely, possibly exclusively, in adipose tissue (Zhang et al., 1994Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (11807) Google Scholar). Circulating concentrations of leptin appeared to mirror fat cell stores—increasing with overfeeding and decreasing with starvation. Leptin administration to obese leptin-deficient animals reversed their hyperphagia, hypothermia, decreased locomotor activity, and all neuroendocrine and immunological abnormalities (Friedman and Halaas, 1998Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4541) Google Scholar). Humans genetically lacking leptin are also hyperphagic and severely obese and respond dramatically to leptin administration (Friedman and Halaas, 1998Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4541) Google Scholar). Administration of leptin to fasted mice abrogates many of the neuroendocrine consequences of starvation, suggesting that the normal biological role of leptin to the in and (Friedman and Halaas, 1998Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4541) Google Scholar). The db/db is to in the for leptin a A of and compound loss-of-function in the leptin have also been in severely obese et al., J.M. B. et and of of the leptin PubMed Scopus Google Scholar). are at least of the leptin a of The is It is in the hypothalamus and on and signals the the of the are more than their are administration of leptin the nervous of ob/ob mice in that in in the the body weight and (Friedman and Halaas, 1998Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4541) Google the of these leptin in most actions of leptin is at food intake and body fat in leptin-deficient and normal it is in in mice with This is in with the observations that in human leptin is with fat leptin administration to obese has a and on body weight. These observations have to the that the to regulate energy stores in of leptin has the for obesity that was it has and It is in with leptin et al., J.M. et of leptin on cell and of human leptin PubMed Google has on the of with of body fat and leptin et al., et for PubMed Scopus Google and a for et al., J.L. R. human leptin in with hypothalamic PubMed Scopus Google Scholar). to of obese have leptin of leptin in these are in with such to weight weight loss. The critical of leptin in the control of energy has been and leptin in the brain to regulate food intake and leptin is leptin the in leptin The hypothalamus and and signals from the In the of the hypothalamus are two of that are the in the brain and regulation of the PubMed Scopus Google Scholar). The first of two the and The the and and the of to the hypothalamus and in the brain Leptin and the of and of or has major on body weight (see and regulation of the PubMed Scopus Google an PubMed Scopus Google mice lacking on in to an in energy expenditure et al., mice an PubMed Scopus Google Scholar). genetically ablated in energy the 2006; PubMed Scopus Google Scholar). the to which were ablated in the was of in adult to these are ablated in the the on body weight and food intake are more suggesting that can in but in It is the of of these on food intake are to the of and or the of is In to are leptin and to influence energy is evidence that peptides a critical role in feeding behavior with mice and hyperphagia and obesity et al., and energy from human and PubMed Scopus Google Scholar). to a of the which are for The of from is influenced a number of the of and and et al., and energy from human and PubMed Scopus Google Scholar). has been the energy recent evidence in appetite at least in et al., A role for in human 2006; PubMed Scopus Google et al., J.M. M. et in the control of human energy 2006; PubMed Scopus Google Scholar). Leptin are also of the the of at these has been For the of leptin in of the in obesity et al., R. Leptin in is required for normal body weight PubMed Scopus Google it is less than in mice that leptin are now to that leptin on such that factor in the ventromedial hypothalamus, are required for normal body weight et al., J.M. et in the and this leptin is required for normal 2006; PubMed Scopus Google Scholar). lacking leptin on these in the ventromedial hypothalamus in food intake. on a these mice to food intake and energy expenditure. leptin in of the ventromedial hypothalamus an role in the critical for is more to mice with a of leptin on and more than with of were less obese than mice that leptin that for leptin such the and the in the The et al., J.M. that the is a for the of leptin on food PubMed Scopus Google and a of the to and the and the a in in in to the the in the was reversed leptin leptin or suggesting that leptin peptides in the hypothalamic et al., L. regulation of leptin in the of the and in the hypothalamic 2006; PubMed Scopus Google Scholar). The that have long been to a role in the and of recent now that these leptin food in a manner et al., L. L. Leptin regulation of the 2006; PubMed Scopus Google et al., R. M. Leptin in 2006; PubMed Scopus Google Scholar). of in mice and in obesity et al., and energy from human and PubMed Scopus Google Scholar). are for to of of obesity and and of adult obesity et al., et and of gene in a and obese from 2006; PubMed Scopus Google et al., of and of with PubMed Scopus Google Scholar). of the in the in the a of et al., et and of and in a PubMed Scopus Google of the most The of hyperphagia, an in fat and and an in et al., J.M. of obesity and in the PubMed Scopus Google Scholar). is the that the of in in can the of food at a the that mutation et al., J.M. of obesity and in the PubMed Scopus Google Scholar). it was to of the of to regions of the control food intake whereas energy are now that is of the et al., M. et of in the control of food intake and energy PubMed Scopus Google Scholar). and mice in the hypothalamus and the than control these mice were than mice lacking This was to a in food intake the energy intake of mice lacking was this in the hypothalamus to control food but have a role in the control of energy expenditure. The that the physiological of in energy are for it is these two et al., and energy from human and PubMed Scopus Google lacking have a an fat their body weight is to mice to a in influence and the of stores A number of recent have the and that the In a body of evidence factor a in energy is a of brain and and its through the and its are in the lacking of the gene or with a of in the brain hyperphagia and obesity et al., M. B. R. R. of factor in the brain to obesity and PubMed Scopus Google Scholar). Administration of can the hyperphagia and in db/db mice et al., Y. M. M. factor energy in diabetic PubMed Scopus Google Scholar). that and in the regulation of energy et al., B. factor energy of PubMed Scopus Google Scholar). et that was in the ventromedial with and The also showed that mice with a mutation in in of mice lacking in that hyperphagia and body and weight on a of mice with deficient the hyperphagia and weight on In of the et al., A mutation human with obesity and PubMed Scopus Google and in its et al., J.M. et and with of of the factor 2006; PubMed Scopus Google hyperphagia and and is an produced in the lateral from that has a critical role in energy an PubMed Scopus Google Scholar). lacking are and whereas of in the lateral hypothalamus to obesity and The role of this in the of leptin is the that is in of ob/ob with a in body fat in ob/ob mice also lacking of the to for the of in hyperphagia, but mice lacking mice a of and of has been to energy and and Friedman J.M. in mice with of 2006; PubMed Scopus Google Scholar). were peptides produced in the lateral hypothalamus et al., M. et and a of hypothalamic and that regulate feeding 1998; PubMed Scopus Google Scholar). administration of appeared to food intake in mice to the that the of was the control of food intake. that a more role in the of with or of in et al., regulation of and PubMed Scopus Google Scholar). A with the leptin and the in that leptin administration whereas et al., M. M. et regulate to energy in PubMed Scopus Google Scholar). The hypothalamic factor is in a number of regions to involved in energy the and the lateral of is with hyperphagic obesity and et al., B.M. J.L. anorexia and of 2006; PubMed Scopus Google et al., J.L. hyperphagia, obesity and of the of the PubMed Scopus Google the of and two of hypothalamic These involved in the regulation of food intake through its mice hyperphagic hypothalamic and have an to suggesting that in the regulate feeding in to et al., B.M. J.L. anorexia and of 2006; PubMed Scopus Google Scholar). have long been to have in the of weight but the through which regulate food intake have remained It now that of with the a of of but it also to an in at in and a in food intake et al., L. J.M. et to food 2006; PubMed Scopus Google Scholar). have leptin can influence and studying the in from ob/ob it was shown that leptin to on but decreasing to et al., M. Friedman J.M. of feeding PubMed Scopus Google Scholar). of administration to ob/ob leptin was to these it to a of Leptin also to a factor hypothalamic et al., of leptin on hypothalamic that regulate PubMed Scopus Google with leptin severely the of from the to the lateral hypothalamus, and regions in the control of energy balance. Leptin in adult in this in in a in leptin in has long been can the of to to that of This to is a critical of hypothalamic in the that have major for energy in this in the obesity in leptin-deficient the that leptin in leptin-deficient with obesity in profound weight et al., M. R. L. et of leptin on and behavior in leptin-deficient Sci. PubMed Scopus Google that a hypothalamic in the of leptin, the ability to respond in a physiological manner to leptin is the factor that a of adult et al., in the hypothalamus of adult role in energy PubMed Scopus Google Scholar). has the ability to weight that the of cell in feeding the hypothalamus, with many of the to critical in energy balance. In the of of an intact leptin and circulating leptin to weight loss. This to the of leptin is to the this A of circulating leptin to its the brain to at in with a of leptin In leptin in rats from decreased of the leptin hypothalamic (see and The role of leptin in feeding and neuroendocrine PubMed Scopus Google an PubMed Scopus Google Scholar). a that has recent is that leptin to an of the leptin of is an that the of It is now to to leptin and is a of leptin of is mice with of or with of are and leptin et al., leptin and of obesity in mice with of PubMed Scopus Google et al., R. leptin and in mice lacking of in 2006; PubMed Scopus Google et al., R. R. in the brain leptin and to PubMed Scopus Google Scholar). et the role in leptin that of from also in leptin and to weight on a recent that that mice with a of the are to leptin to this an role in the of leptin et al., M. B. body and leptin 2006; PubMed Scopus Google Scholar). Leptin In this is of the of the in and the of in a of involved in leptin In to the of the of the with of rapidly the of or it is to or in this The is a endocrine cell and leptin is in endocrine The of leptin produced an to at the but also at the of and and regulation of leptin and feeding and in adipose 2006; PubMed Scopus Google Scholar). Leptin but this to in and regulate leptin whereas that in the such leptin et al., Y. leptin from and human adipose tissue through PubMed Scopus Google Scholar). The marked in in than at least in a of on leptin The fat stores are to the adipose tissue to more leptin and has been of leptin in the cell in which cell has been is an that has been proposed to an role in energy and from an to of the PubMed Scopus Google Scholar). It has with and and and its has a that In to leptin, are with body decreasing with obesity and in to weight loss. also in at a than leptin from mouse that is the of and et al., et lacking decreased and to Biol. 2006; PubMed Scopus Google Scholar). the evidence that has a role in food intake is less of can food intake in rats and the of obesity et al., M. M. of the of obesity in Sci. PubMed Scopus Google food intake in mice is from that in et al., M. M. Y. et in mice lacking PubMed Scopus Google Scholar). is a that has in and the It is also secreted from adipose fat (the fat the of leptin, with body lacking are hyperphagic but obese in adult a of in energy expenditure et al., B. M. mice PubMed Scopus Google Scholar). a of and hyperphagia and a more marked obesity et al., Y. and obesity in 2006; PubMed Scopus Google Scholar). In of the to hyperphagia and the administration of hyperphagia in mice but it is the et al., et of in mice to hyperphagia, obesity and 2006; PubMed Scopus Google Scholar). This that have a role in the regulation of food intake the is a that has long been to a satiety et al., hormones regulating R. Soc. Lond. Biol. Sci. 2006; PubMed Scopus Google Scholar). It is the from of the and in to at on afferent which to appetite such the of the tract, the administration of also mouse in the of the with in this to in the satiety of This is in food intake in mice lacking and in mice in which are et al., of feeding the PubMed Scopus Google Scholar). in to signals leptin, the also in satiety is a secreted from the endocrine of the Circulating are in the and rapidly two and are the peptides have on and have the ability to food intake the of In can food intake et al., hormones regulating R. Soc. Lond. Biol. Sci. 2006; PubMed Scopus Google leptin, the of were to through the system. this to the a the of et al., and energy from human and PubMed Scopus Google Scholar). have in the of et al., M. et food intake in PubMed Scopus Google a that the influence of on the ability of the animals to It has been that the of food intake is at least in on the of an and administration of in PubMed Scopus Google Scholar). recent from a mouse have evidence that have a physiological role in in the of et al., role for in satiation and 2006; PubMed Scopus Google Scholar). In are in many that are weight loss. have been to have a of with satiety et al., M. in obese is with 2006; PubMed Scopus Google and in an the of such in a in weight et al., an weight and 2006; PubMed Scopus Google Scholar). or is a physiological of food of an are and the are with great was an for the The is produced and secreted the of the and are weight and administration of food intake and fat has been proposed to an involved in energy in that it appetite than a satiety and of in and Scopus Google Scholar). is evidence to that the are to on food intake and of in and Scopus Google Scholar). the first of mice with of in feeding behavior or body were et al., Y. of Biol. PubMed Scopus Google et al., L. R. M. et of food intake but Sci. PubMed Scopus Google Scholar). animals were also et al., Y. of and appetite is through the Sci. PubMed Scopus Google Scholar). more of the of mice lacking et al., of PubMed Scopus Google or et al., J.M. Y. R. et lacking the of PubMed Scopus Google that are to obesity a less and more fat an energy than These to the that are an of coordinated has been a that rats with can to the and that this is with decreased of weight et al., the weight Sci. 2006; PubMed Scopus Google Scholar). In to produced in the also produced the A of the hypothalamus, the and were et al., M. M. M. et and of of in the a hypothalamic regulating energy PubMed Scopus Google Scholar). The of to is now evidence that the actions of are of physiological in the control of et al., R. et in the brain 2006; PubMed Scopus Google Scholar). of the and in adipose tissue but also of and in in with a in energy expenditure. to toward fat an in and and in This in with the of mice of the and to a decreased to this also an role for the in than a of this change in circulating in the processes that the body to and is from the of the A recent et has that but of this a that the of on food intake (Zhang et al., R. a the on food PubMed Scopus Google Scholar). a to for in of et a of that is of the revealed it to a circulating peptide, was also the of In with a of the that it food and decreased body all in to the of the of these on food intake the was named from the a of et showed that appeared to a that is in the in the and the it appeared that two hormones were from the with in with this an to of to have such a In the mice were also deficient in the the biological of For example, the circulating of to than of and in to to change in circulating or in these to in the the of the more recent that have to of on food intake in et al., B. L. R. is but PubMed Scopus Google et al., R. M. et of on energy and in PubMed Scopus Google Scholar). is a of the from the of the in to food The of 2006; PubMed Scopus Google Scholar). is a of This has to the of that have in the of The of 2006; PubMed Scopus Google Scholar). can also influence food intake with the capable of and body weight in obese diabetic The on body weight a of of satiety of but is also evidence that can influence feeding behavior at the of the in the and the of the hypothalamus et al., hormones regulating R. Soc. Lond. Biol. Sci. 2006; PubMed Scopus Google Scholar). is also produced from the gene and from the in to a it to and a for has to from and human that administration of can food intake and body weight with of these a of the et al., hormones regulating R. Soc. Lond. Biol. Sci. 2006; PubMed Scopus Google Scholar). are in the brain with the concentrations in the and the the The of that appeared to respond to and regulate food intake and adipose was many years before leptin was et al., in the a of energy Google Scholar). Despite of has on food intake and body weight et al., M. R. of brain in control of body weight and PubMed Scopus Google Scholar). mice with of the gene in the hyperphagic and than but this a endocrine The of a more of in the hypothalamus, has been et al., L. hypothalamic hyperphagia and in PubMed Scopus Google were to hypothalamic the an to the of in This resulted in a and hyperphagia, with an in the of and the role of at is et al., M. M. M. et role of in hypothalamic and cell PubMed Scopus Google generated mice that lacked in is a major of the of In to the of leptin from mice lacking from these hyperphagic suggesting that in a major role in energy from in to leptin, and the that the of are to et al., L. B. R. M. R. et in and to 2006; PubMed Scopus Google Scholar). many of and it is to role in the normal of energy has a major and role in the control of the of in the has to the the physiological of such actions is from at the of in proportion to the of with the of has an physiological role in the control of food intake of the can food intake in et al., hormones regulating R. Soc. Lond. Biol. Sci. 2006; PubMed Scopus Google Scholar). Circulating of from the are to appetite et al., and in PubMed Scopus Google Scholar). is a of the in whereas an excess of can also have a the system. the obese in leptin-deficient ob/ob mice and the in and the in in ob/ob mice hypothalamic et al., obese and hypothalamic in leptin-deficient ob/ob PubMed Scopus Google Scholar). In the of the is in rats but with of et al., the of the nervous PubMed Scopus Google Scholar). hormones from the have also been in the of recent have shown that can body weight This in in a in energy intake and an in energy expenditure et al., Y. Y. J.L. et on the of and in obese PubMed Scopus Google Scholar). hormones can influence feeding in the is to food intake et al., food intake the hypothalamic ventromedial of in energy PubMed Scopus Google Scholar). this the that a marked in and in food intake a to this in energy expenditure. has been with and of et al., M. et of leptin through of with 2006; 425-432Crossref PubMed Scopus Google have that leptin, that this leptin in and that leptin from This a in which the of leptin to the of of a leptin a to leptin in obese the and leptin For example, we have that with leptin are with leptin is change in circulating concentrations and leptin an physiological of PubMed Scopus Google and we have been to of leptin actions in mice with leptin and a excess of et al., leptin an physiological of PubMed Scopus Google Scholar). The evidence for a critical role of leptin and its in the control of food intake is and of a with The and hyperphagia in and the leptin is which in the of of the adipose tissue that signals at most a role in control of food intake. In the evidence for such a role in appetitive control is of a in which is a of this a physiological role for such it the of an in which signals provide to the brain the of whereas a of signals have in and experiments toward the of and peptides the of the in and understanding of the normal of energy and the endocrine control of food intake have profound for the of and for human to obesity is a that has appeared a of a have of with a of with at the of the in the and of food and the in physical and have to an in the of in with substantial obesity is a proportion of are The of is and the most is that genetically in the homeostatic energy the in or to an that a the that body weight can of human but the that the with which this can and that are to on the of biological This to the of obesity Friedman has on the J.M. A on the PubMed Scopus Google Scholar).