Diabetes, a new mutation in the mouse. Glucagon and epinephrine levels rise during fasting and stimulate hunger. Sex steroids have profound effects on appetite. However, it was subsequently revealed that deficiency of insulin receptors or PI3 kinase in POMC and AGRP neurons did not affect feeding or weight [ 53 , 55 , 56 ], suggesting that central insulin does not play a critical role in the long-term regulation of energy homeostasis. Nutrient signals that indicate fullness, and therefore inhibit hunger include the following: How do I know when I am overeating?
How weight loss affects our hormones
Furthermore, because of the redundant neuronal and hormonal mechanisms in the gut, it is doubtful that targeting a limited number of peptides is a viable therapeutic approach. Indeed, genetic manipulation of anorexigenic gut hormones rarely causes overt changes in feeding, weight and metabolism [ 29 , 30 , 32 ]. However, gut hormone alterations may explain the rapid effects of Roux-en-Y gastric bypass surgery to decrease weight and reverse diabetes [ 33 , 34 ].
GLP-1 is increased after gastric bypass surgery, and may inhibit appetite and augment insulin secretion [ 34 ]. Efforts are underway to target ghrelin for the treatment of anorexia and cachexia. Ghrelin antagonists have the potential for obesity and diabetes therapy. As mentioned earlier, the discovery of leptin was a major milestone in elucidation of the communication between the brain and energy stores.
Leptin is expressed by adipocytes and the concentrations of leptin in adipose tissue and plasma parallel the mass of adipose tissue and triglyceride content. Thus, leptin is increased in obesity and falls with weight loss [ 35 , 36 ].
These changes are partly mediated by insulin. Leptin is transported via a saturable process across the blood-brain barrier. Moreover, the circumventricular organs, e. The most abundant short leptin receptor, LRa, which lacks the cytoplasmic domain necessary for Janus family of tyrosine kinases JAK -signal transducer and activator of transcription STAT signaling, may mediate leptin transport across brain capillaries.
The long leptin receptor, LRb, is highly expressed in the hypothalamus, brainstem, and several regions of the brain that control feeding, energy expenditure and hormones [ 35 ].
Binding of leptin to LRb results in autophosphorylation of JAK2, phosphorylation of the tyrosine residues and on LRb, activation and nuclear translocation of STAT3, and transcription of neuropeptides [ 36 ]. Leptin-mediated activation of STAT5 and protein-tyrosine phosphatase 1B also terminates leptin signaling [ 36 ].
Neuronal targets for leptin have been mapped in the brain using anatomical, pharmacological and molecular genetic techniques. These neurons project to the paraventricular nucleus PVN , which controls feeding and also provides preganglionic autonomic output to the brainstem. NPY stimulates food intake, reduces energy expenditure and increases weight via Y1 and Y5 receptors. Melanin concentrating hormone MCH and orexins are expressed in distinct populations of neurons in the lateral hypothalamic area.
The targets of the MCH and orexin neurons include the trigeminal, facial, and hypoglossal motor nuclei that control licking, chewing and swallowing, and parasympathetic preganglionic nuclei in the medulla that control salivation, gut motility and gut secretions. MCH and orexin neurons also communicate with noradrenergic neurons in the locus coeruleus, serotoninergic neurons in the dorsal and median raphe nuclei, and the histaminergic tuberomammillary nucleus.
These monoaminergic systems regulate arousal. In addition, the MCH and orexin neurons project diffusely to the cerebral cortex, likely to regulate complex behaviors in relation to sleep-wake cycles.
The significance of hypothalamic neuropeptides in energy homeostasis has been ascertained using gene ablation methods in mice [ 37 - 42 ]. On the other hand, the lack of POMC or functional melanocortin-4 receptor caused hyperphagia and obesity [ 41 , 42 ]. Reduced leptin levels during fasting also stimulate MCH and orexins in the lateral hypothalamic area. Hypothalamic leptin signal transduction.
These changes in neuropeptide expression culminate in satiety, stimulation of energy expenditure and weight loss. As with other complex diseases, obesity is influenced by polygenic and environmental factors, particularly energy-dense food and sedentary life style. Diet-induced obesity in rodents is characterized by increased leptin levels, reduced leptin transport across the blood-brain-barrier, and impaired leptin signaling in the hypothalamus, related to induction of SOCS3 [ 35 , 36 ].
Deletion of SOCS3 in leptin-responsive neurons in the arcuate nucleus enhanced leptin sensitivity and protected against diet-induced obesity and diabetes [ 43 , 44 ].
Leptin exerts rapid effects on neurotransmission [ 45 ]. This pattern was rapidly reversed by leptin treatment within 6 hours, suggesting that leptin-mediated synaptic plasticity preceded the appetite-suppressing effect of the hormone [ 47 ].
In contrast to leptin, the stimulatory effect of ghrelin on food intake has been associated with a net increase in synaptic activity in the hypothalamus [ 27 ]. These results indicate that peripheral metabolic hormones can alter brain function through modulation of synaptic function [ 27 , 47 ]. Recent studies have focused attention on the actions of leptin in the human brain [ 48 - 50 ]. Restoration of leptin levels maintained the weight reduction, as well as normalized brain activity patterns [ 48 ].
Congenital leptin deficiency is associated with reduced brain activity in regions related to hunger, and increased brain activity in regions linked to satiety [ 49 , 50 ]. Insulin is secreted in response to meals and increases the storage of glycogen, fat and protein.
In peripheral tissues, insulin autophosphorylates the insulin receptor, leading to activation of the insulin receptor substrate IRS -phosphatidylinositol 3-kinase PI3K enzyme system. Studies by Porte and his colleagues, preceding the discovery of leptin revealed a blood-to-brain insulin transport, and binding of insulin to several regions in the brain [ 51 ]. Most significantly, injection of insulin into the cerebral ventricle or directly into the brain parenchyma profoundly inhibited food intake [ 51 ].
We now know that insulin signaling molecules are expressed in key hypothalamic nuclei involved in energy metabolism [ 52 ]. Insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3 kinase, and activates Akt Fig. Pharmacological inhibition of PI3 kinase prevented the satiety effect of central insulin [ 52 ]. Studies also indicate a cross-talk between leptin and insulin signaling in the hypothalamus [ 52 ] Fig.
Deletion of insulin receptors in neurons resulted in a mildly obese phenotype in female mice [ 54 ]. However, it was subsequently revealed that deficiency of insulin receptors or PI3 kinase in POMC and AGRP neurons did not affect feeding or weight [ 53 , 55 , 56 ], suggesting that central insulin does not play a critical role in the long-term regulation of energy homeostasis.
Cross-talk between insulin and leptin signaling in the hypothalamus. The endocannabinoid system has significant effects on appetite and metabolism [ 57 ]. Endocannabinoids bind to cannabinoid receptors type 1 and type 2 CB1 and CB2 receptors. The CB1 receptor, a G-protein coupled receptor, is widely expressed in the brain and peripheral tissues, and is thought to mediate the metabolic actions of endocannabinoids.
Overnutrition activates the endocannaboid system, which results in hyperphegia, reduction in energy expenditure and obesity [ 57 ]. Stimulation of CB1 receptor with anandamide increases food intake and weight in rodents. Conversely, CB1 receptor antagonists suppress feeding and decrease weight [ 57 ]. Rimonabant, a CB1 receptor blocker, inhibits appetite and decreases weight in obese patients [ 58 ]. In addition, rimonabant decreases glucose and lipids [ 58 ]. Adiponectin is secreted by adipocytes and circulates in the plasma in the form of homotrimers, low-molecular weight hexamers and high-molecular weight HMW complexes [ 59 ].
In contrast to leptin, adiponectin is reduced in obesity and increased in response to fasting [ 59 ]. Adiponectin deficiency induces insulin resistance and hyperlipidemia, and is associated with increased susceptibility toward vascular injury and atherosclerosis [ 59 ]. Insulin-sensitizing thiazolidinediones increase HMW adiponectin in humans and rodents. Adiponectin signaling is mediated via two seven-transmembrane domain-containing proteins, AdipoR1 and AdipoR2, which are widely expressed, and induce AMP kinase phosphorylation and activity [ 59 ].
AdipoR1 and R2 are expressed in the brain, although adiponectin did not cross the blood-brain barrier in mice [ 59 , 60 ]. However, several lines of evidence support the notion that adiponectin acts centrally. Trimeric and low molecular weight adiponectin are present in cerebrospinal fluid in humans and rodents [ 61 - 63 ], and the concentration of adiponectin in cerebrospinal fluid increases following intravenous injection of adiponectin [ 62 , 63 ].
Intracerebroventricular administration of adiponectin stimulated energy expenditure [ 62 ] and reduced food intake [ 64 ]. The ability of adiponectin to decrease food intake was dependent on AdipoR1 [ 64 ]. Adiponectin has been proposed as a mediator of the metabolic response to fasting [ 63 ]. When adiponectin was administered peripherally to mimic rising levels during fasting, this resulted in an increase in food intake, reduction in energy expenditure, and weight increase [ 63 ].
Adiponectin also activates area postrema neurons expressing both AdipoR1 and AdipoR2, and inhibits oxytocin neurons in PVN [ 65 , 66 ]. Whether these actions are involved in regulation of feeding and energy homeostasis remains to be determined.
Glucocorticoid excess increases feeding, weight and fat [ 67 ]. When administered in the brain, glucocorticoids have a permissive action on the transcription of NPY in the hypothalamus, and also modulate the levels of monoamines in the mesolimbic reward pathways, to increase the consumption of palatable food [ 67 ].
In contrast, adrenalectomy decreases food intake and weight, even in the most severe form of obesity resulting from leptin deficiency [ 68 ]. Sex steroids have profound effects on appetite. Peripheral estrogen treatment enhanced the anorexigenic actions of leptin and insulin in ovariectomized female rats as well as intact males [ 69 ].
Administering estradiol directly into the brain of female rats increased the sensitivity to central leptin while reducing insulin sensitivity [ 69 ]. Estradiol acted in the brain to increase subcutaneous fat [ 69 ].
Ciliary neurotrophic factor CNTF induces weight loss. However, the satiety and anti-obesity affects of CNTF persist after the cessation of treatment [ 71 ]. CNTF also induces cell proliferation in mouse hypothalamus, and several of the newly formed cells are capable of responding to leptin [ 72 ]. Thus, CNTF-induced neurogenesis may affect of feeding behavior [ 72 ]. These cytokines inhibit feeding and induce thermogenesis, partly by modulating the expression of hypothalamic neurotransmitters [ 73 , 74 ].
Eating provides energy substrates for metabolism, thus it is logical that eating behavior is subject to homeostatic controls described in the preceding sections. However, appetite is also driven by factors beyond physiological needs.
Food provides powerful visual, smell and taste signals which can override satiety and stimulate feeding. We tend to overeat sweet and salty foods and consume less of foods that are bitter or sour. The taste and smell of food can profoundly alter behavior, so that palatable food is sought after while unpleasant food induces aversion. A variety of taste receptors, including the classic sweet, salty, sour, bitter tastes, are expressed by taste cells in the tongue and oral cavity, which convey the information to the NTS and parabrachial nucleus in the brainstem.
Taste sensation is then relayed to the thalamus and lateral frontal cerebral cortex, central nucleus of the amygdala and lateral hypothalamus area. Neuropeptides implicated in the signaling of taste include substance P, cholecystokinin CCK and opioids. Leptin is able to modulate taste perception, as evidenced by increased response to sweet taste in mice lacking leptin [ 75 ]. Psychotropic drugs affect feeding and weight [ 76 ]. Studies in animals have suggested that drug and food rewards share similar neuronal pathways.
For example, the ability AGRP to increase feeding is blocked by naloxone, an opioid antagonist [ 77 ]. Serotonin 5-HT2C receptor agonist inhibits food intake partly by activating melanocortin 4 receptors [ 79 ]. In mice, leptin inhibits the motivation to feed by activating dopamine and GABA expressing neurons in the mesolimbic pathway [ 80 , 81 ].
A similar action has been observed in patients with congenital leptin deficiency whereby brain activity was increased in the ventral striatum, and this was associated with an increase in the drive to eat even when the patients has just eaten [ 50 ].
Eating behavior is critical for the acquisition of energy substrates. As discussed in this review, the gut—brain axis controls appetite and satiety via neuronal and hormonal signals. The entry of nutrients in the small intestine stimulates the release of peptides which act as negative feedback signals to reduce meal size and terminate feeding. Hormones and cytokines secreted by peripheral organs exert long-term effects on energy balance by controlling feeding and energy expenditure.
Neurons involved in the homeostatic regulation of feeding are located mainly in the hypothalamus and brainstem. In addition, neuronal circuits in the limbic system mediate the motivational and reward aspects of feeding.
Insights into how peripheral metabolic signals interact with the brain will be gained from brain imaging and metabolic studies in humans, and preclinical experimentation in animal models, utilizing molecular, genetic, physiological and behavioral tools.
Knowledge of the neurobiological basis of eating will promote the understanding and rational treatment of disorders of energy homeostasis, such as obesity and cachexia. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.
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National Center for Biotechnology Information , U. Endocrinol Metab Clin North Am. Author manuscript; available in PMC Dec 1. See other articles in PMC that cite the published article. Abstract Interest in the control feeding and has increased as a result of the obesity epidemic and rising incidence of metabolic diseases. Nervous system, appetite, metabolism, adipokine, neuropeptide.
Historical perspective Our survival depends on the ability to procure food for immediate metabolic needs and to store excess energy in the form of fat to meet metabolic demands during fasting. Gut-brain connection The gastrointestinal tract acts not only as a conduit for food, but is also crucial for the digestion and absorption of nutrients.
Leptin-brain interaction As mentioned earlier, the discovery of leptin was a major milestone in elucidation of the communication between the brain and energy stores.
Open in a separate window. Other peripheral factors controlling feeding and metabolism Insulin is secreted in response to meals and increases the storage of glycogen, fat and protein. Hedonic mechanisms regulating appetite and satiety Eating provides energy substrates for metabolism, thus it is logical that eating behavior is subject to homeostatic controls described in the preceding sections.
Conclusion Eating behavior is critical for the acquisition of energy substrates. From lesions to leptin: The effects of lesions in the hypothalamus in parabiotic rats. The glucostatic theory of regulation of food intake and the problem of obesity a review Nutr Rev. The role of depot fat in the hypothalamic control of food intake in the rat. Obese, a new mutation in the house mouse.
Diabetes, a new mutation in the mouse. Effects of parabiosis of obese with diabetes and normal mice. Effects of parabiosis of normal with genetically diabetic mice. Positional cloning of the mouse obese gene and its human homologue. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB leptin receptor. The role of gastrointestinal vagal afferents in the control of food intake: Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin in rats.
Capsaicin application to central or peripheral vagal fibers attenuates CCK satiety. Delay in meal termination follows blockade of N-methyl-D-aspartate receptors in the dorsal hindbrain. Satiation At some point during a meal, the brain receives signals that enough food has been eaten. Satiation occurs; the eater feels full and stops eating. Did My Stomach Shrink? Changes in food intake cause rapid adaptations in the body. At some point in food deprivation, hunger returns with a vengeance and can lead to bouts of extensive overeating.
This observation may partly explain the increasing U. Satiety After finishing a meal, the feeling of satiety continues to suppress hunger over a period of hours, regulating the frequency of meals.
Hormones, nervous signals, and the brain work in harmony to sustain feelings of fullness. Leptin, one of the adipokine hormones, is produced in direct proportion to body fatness. Energy Nutrients and Satiety The composition of a meal seems to affect satiation and satiety, but the relationships are complex.
Of the three energy-yielding nutrients, protein seems to have the greatest satiating effect during a meal. Many carbohydrate-rich foods, such as those providing slowly digestible carbohydrate and soluble fiber, also contribute to satiation and satiety. Researchers have also reported increased satiety from foods high in water and even from foods that have been puffed up with air.