Trends in Pharmacological Sciences
ReviewSpecial issue: Pharmacology in The NetherlandsAnti-obesity drugs and neural circuits of feeding
Introduction
Obesity is a risk factor for the development of diseases such as type II diabetes, stroke, cardiovascular disease and certain forms of cancer. We believe that being lean is a physical state to which many overweight individuals aspire. Dieting and exercising to lose weight require effort, willpower and persistence, making weight-reducing drugs an extremely attractive option (Table 1). The obesity epidemic has boosted the interest of the pharmaceutical industry in the development of anti-obesity drugs.
The discovery of drugs that have entered the market for the treatment of obesity is characterized by serendipity. Fenfluramine and sibutramine were discovered during the search for new antidepressants, and rimonabant was developed for smoking cessation, among other indications. When it was discovered that these drugs reduce food intake and induce weight loss, focus was turned towards the treatment of obesity 1, 2, 3.
Obesity is caused by energy intake (by ingestion) exceeding energy expenditure (by basal metabolic rate, diet-induced thermogenesis and exercise), with surplus energy stored in the form of fat. Over the past six decades, research has unraveled neural circuits that are implicated in the regulation of feeding. The entry of food into the stomach and intestines and the delivery of nutrients to the liver generate neural signals to the brainstem, via the vagal nerve, that have a role in the termination of a meal. The destruction of these neural inputs by vagal nerve cutting results in greater food intake (by increased meal size and frequency) [4]. Rats with knife-cut lesions between the brainstem and the midbrain (caudal–hypothalamus) do not increase meal size when food is restricted, as hungry rats normally do [5]. These data implicate the involvement of neural circuits in the brainstem during satiation (the process that limits meal size) but not during hunger, for which more-rostral neural circuits are required.
Electrical lesioning and stimulation studies in the hypothalamus have identified several nuclei that are important in the regulation of feeding behavior. Electrolytic destruction of the ventromedial hypothalamus increases feeding behavior (by causing meals to be eaten more frequently) and induces obesity 6, 7, 8. In addition, lesions of the hypothalamic paraventricular nucleus (PVN) and the arcuate nucleus (ARC), which are highly interconnected nuclei, also result in hyperphagia and obesity 9, 10. Moreover, electrical stimulation studies of the lateral hypothalamus (LH) activated a motor program that elicits feeding and hoarding even when sated [11], emphasizing the role of this nucleus in meal initiation and hunger signaling. Overall, these data implicate the hypothalamus in (the initiation of) feeding behavior.
In addition to the homeostatic control of feeding, which involves the brainstem and the hypothalamus, animals – including humans – also eat because palatable food is rewarding. It is hypothesized that this is because of the hedonic value of food [12]. Food reward and the anticipation of meals implicate the nucleus accumbens (NAcc) – a brain structure that is important in reward processing – in the control of food intake 13, 14. The NAcc is connected to both cortical and limbic brain regions such as the amygdala and orbitofrontal cortex (OFC), the LH and ventral tegmental area (VTA) [15], and is implicated in motivation to eat [16].
In this article, we describe how peripheral signals that affect energy balance modulate neural circuits. We then delineate the functional role of these circuits and describe how they are targets for anti-obesity drugs. Although anti-obesity drugs also have peripheral modes of action, we focus on the central mechanisms by which they affect food intake.
Section snippets
Peripheral hormones involved in satiation
Gastrointestinal and pancreatic hormones such as cholecystokinin (CCK), amylin, insulin and glucagon are released during, or in anticipation of, meals and act to limit meal size (reviewed in Refs 17, 18, 19). Other hormones that affect meal size are peptide YY (PYY)3–36, glucagon-like peptide (GLP)-1 and oxyntomodulin, which are released from distal intestinal L-cells. Levels of these hormones increase following meals and remain elevated for several hours (reviewed in Ref. [18]) (Figure 1a).
Targeting obesity
The discovery of leptin and other hormones involved in energy balance led to new opportunities for developing drugs to treat obesity (Table 2). Drugs that mimic the action of CCK, GLP-1, amylin and PYY3–36 could increase feelings of satiation and satiety, and antagonists of ghrelin receptors could decrease feelings of hunger (reviewed in Ref. [23]). Thus, these drugs would decrease appetite and caloric intake. CCK has an established role in satiation and satiety but, despite treatment with this
Concluding remarks
Research in recent years has further elucidated neural circuits that regulate food intake, providing a framework for understanding how drugs that suppress food intake function. Although these neural circuits do not act independently, from a drug discovery point of view, there are at least three levels at which ingestive behavior can be targeted: brainstem, hypothalamus and limbic corticostriatal system. These neural circuits use partially different signaling molecules. Anti-obesity drugs
References (124)
Influence of anterior subdiaphragmatic vagotomy and TPN on rat feeding behavior
Physiol. Behav.
(1992)Hypothalamic paraventricular nucleus lesions produce overeating and obesity in the rat
Physiol. Behav.
(1981)- et al.
Adiposity signals and the control of energy homeostasis
Nutrition
(2000) - et al.
Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measured by microdialysis
Life Sci.
(1988) Entrainment by a palatable meal induces food-anticipatory activity and c-Fos expression in reward-related areas of the brain
Neuroscience
(2005)- et al.
Connections of the nucleus accumbens
Brain Res.
(1976) Corticostriatal–hypothalamic circuitry and food motivation: integration of energy, action and reward
Physiol. Behav.
(2005)- et al.
Appetite signaling: from gut peptides and enteric nerves to brain
Physiol. Behav.
(2007) - et al.
Short-term receptor trafficking in the dorsal vagal complex: an overview
Auton. Neurosci.
(2006) Cerebral hemisphere regulation of motivated behavior
Brain Res.
(2000)
Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size
Physiol. Behav.
Leptin regulation of neuroendocrine systems
Front. Neuroendocrinol.
Ghrelin and the short- and long-term regulation of appetite and body weight
Physiol. Behav.
Pharmacological and molecular characterization of ATP-sensitive K+ conductances in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus
Neuroscience
MCH-R1 antagonists: what is keeping most research programs away from the clinic?
Drug Discov. Today
Meal size of high-fat food is reliably greater than high-carbohydrate food across externally-evoked single-meal tests and long-term spontaneous feeding in rat
Appetite
Resistance and susceptibility to weight gain: individual variability in response to a high-fat diet
Physiol. Behav.
Changes in food intake in response to stress in men and women: psychological factors
Appetite
Pharmacological characterization of high-fat feeding induced by opioid stimulation of the ventral striatum
Physiol. Behav.
Amygdala–frontal interactions and reward expectancy
Curr. Opin. Neurobiol.
Orbitofrontal cortex, associative learning, and expectancies
Neuron
Orexin A in the nucleus accumbens stimulates feeding and locomotor activity
Brain Res.
Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA
Bioorg. Med. Chem.
Serotonin and the orchestration of energy balance
Cell Metab.
Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study
Neuroscience
Norepinephrine and the control of food intake
Nutrition
Postsynaptic α2-noradrenergic receptors mediate feeding induced by paraventricular nucleus injection of norepinephrine and clonidine
Eur. J. Pharmacol.
Modulation of feeding by hypothalamic paraventricular nucleus α1- and α2-adrenergic receptors
Life Sci.
Short-term receptor trafficking in the dorsal vagal complex: an overview
Auton. Neurosci.
Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding behaviour
Brain Res.
Sibutramine in weight control: a dose-ranging, efficacy study
Clin. Pharmacol. Ther.
Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors
Psychopharmacology (Berl.)
Facilitory effect of Δ9-tetrahydrocannabinol on hypothalamically induced feeding
Psychopharmacology (Berl.)
Neurological dissociation of gastrointestinal and metabolic contributions to meal size control
Behav. Neurosci.
Hypothalamic lesions and adiposity in the rat
Anat. Rec.
Meal taking and regulation of food intake by normal and hypothalamic hyperphagic rats
J. Comp. Physiol. Psychol.
Weight regulation in normal and hypothalamic hyperphagic rats
J. Comp. Physiol. Psychol.
Hypothalamic obesity: multiple routes mediated by loss of function in medial cell groups
Endocrinology
Lateral hypothalamus: hoarding behavior elicited by electrical stimulation
Science
Pancreatic signals controlling food intake: insulin, glucagon and amylin
Philos. Trans. R. Soc. Lond. B Biol. Sci.
Gastrointestinal hormones and regulation of food intake
Horm. Metab. Res.
Distributed neural control of energy balance: contributions from hindbrain and hypothalamus
Obesity
Gut peptide signaling in the controls of food intake
Obesity
Gut hormones and the regulation of energy homeostasis
Nature
Gastrointestinal regulation of food intake
J. Clin. Invest.
Peptide YY3-36 inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys
Am. J. Physiol. Regul. Integr. Comp. Physiol.
The neuroscience of natural rewards: relevance to addictive drugs
J. Neurosci.
High-fat meals reduce 24-h circulating leptin concentrations in women
Diabetes
Leptin activates neurons in ventrobasal hypothalamus and brainstem
Endocrinology
Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through extracellular signal-regulated kinase signaling in rat solitary nucleus
Endocrinology
Cited by (83)
Quality of Life in Craniopharyngioma: A Systematic Review
2022, World NeurosurgeryThe role of the nucleus accumbens and ventral pallidum in feeding and obesity
2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry‘Liking’ and ‘wanting’ in eating and food reward: Brain mechanisms and clinical implications
2020, Physiology and BehaviorCitation Excerpt :Similarly in people, inducing suppression of dopamine signaling in ordinary volunteers may actually cause them to eat less rather than to eat more [425]. As a caveat, however, the brain has multiple anatomical dopamine systems, and dopamine and norepinephrine signaling in the paraventricular nucleusof medial hypothalamus can oppositely suppress food intake [426,427]. Appetite-suppressing action of dopamine in the paraventricular nucleus of hypothalamus may explain why amphetamine-type drugs can be dieting aids (i.e., by stimulating hypothalamic dopamine and norepinephrine systems), and conversely why long-term exposure to neuroleptic/anti-psychotic dopamine antagonist drugs can sometimes produce weight gain [428–430].
Microstructure analysis of sucrose ingestion in the course of chronic treatment with imipramine
2020, Physiology and BehaviorExploiting common aspects of obesity and cancer cachexia for future therapeutic strategies
2020, Current Opinion in Pharmacology