Huiyuan Zheng

Appetite control and energy balance regulation in the modern world: reward-driven brain overrides repletion signals

Powerful biological mechanisms evolved to defend adequate nutrient supply and optimal levels of body weight/adiposity. Low levels of leptin indicating food deprivation and depleted fat stores have been identified as the strongest signals to induce adaptive biological actions such as increased energy intake and reduced energy expenditure. In concert with other signals from the gut and metabolically active tissues, low leptin levels trigger powerful activation of multiple peripheral and brain systems to restore energy balance. It is not just neurons in the arcuate nucleus, but many other brain systems involved in finding potential food sources, smelling and tasting food, and learning to maximize rewarding effects of foods, that are affected by low leptin. Food restriction and fat depletion thus lead to a ‘hungry’ brain, preoccupied with food. By contrast, because of less (adaptive thrifty fuel efficiency) or lost (lack of predators) evolutionary pressure, the upper limits of body weight/adiposity are not as strongly defended by high levels of leptin and other signals. The modern environment is characterized by the increased availability of large amounts of energy-dense foods and increased presence of powerful food cues, together with minimal physical procurement costs and a sedentary lifestyle. Much of these environmental influences affect cortico-limbic brain areas concerned with learning and memory, reward, mood and emotion. Common obesity results when individual predisposition to deal with a restrictive environment, as engraved by genetics, epigenetics and/or early life experience, is confronted with an environment of plenty. Therefore, increased adiposity in prone individuals should be seen as a normal physiological response to a changed environment, not in the pathology of the regulatory system. The first line of defense should ideally lie in modifications to the environment and lifestyle. However, as such modifications will be slow and incomplete, it is equally important to gain better insight into how the brain deals with environmental stimuli and to develop behavioral strategies to better cope with them. Clearly, alternative therapeutic strategies such as drugs and bariatric surgery should also be considered to prevent or treat this debilitating disease. It will be crucial to understand the functional crosstalk between neural systems responding to metabolic and environmental stimuli, i.e. crosstalk between hypothalamic and cortico-limbic circuitry.

Orexin Signaling in the Ventral Tegmental Area Is Required for High-Fat Appetite Induced by Opioid Stimulation of the Nucleus Accumbens

The overriding of satiety and homeostatic control mechanisms by cognitive, rewarding, and emotional aspects of palatable foods may contribute to the evolving obesity crisis, but little is known about neural pathways and mechanisms responsible for crosstalk between the “cognitive” and “metabolic” brain in the control of appetite. Here we show that neural connections between the nucleus accumbens and hypothalamus might be part of this link. Using the well known model of selective stimulation of high-fat intake induced by intra-accumbens injection of the μ-opioid receptor agonist d-Ala2-N-Me-Phe4-gly5-ol-enkephalin (DAMGO), we demonstrate that orexin signaling in the ventral tegmental area is important for this reward-driven appetite to override metabolic repletion signals in presatiated rats. We further show that accumbens DAMGO in the absence of food selectively increases the proportion of orexin neurons expressing c-Fos in parts of the perifornical hypothalamus and that neural projections originating in DAMGO-responsive sites of the nucleus accumbens make close anatomical contacts with hypothalamic orexin neurons. These findings suggest that direct accumbens–hypothalamic projections can stimulate hypothalamic orexin neurons, which in turn through orexin-1 receptor signaling in the ventral tegmental area and possibly other sites interfaces with the motivational and motor systems to increase intake of palatable food.

Vanilloid receptor (VR1) expression in vagal afferent neurons innervating the gastrointestinal tract.

The vanilloid receptor VR1 is a nonselective cation channel activated by capsaicin as well as increases in temperature and acidity, and can be viewed as molecular integrator of chemical and physical stimuli that elicit pain. The distribution of VR1 receptors in peripheral and central processes of rat primary vagal afferent neurons innervating the gastrointestinal tract was investigated by immunohistochemistry. Forty-two percent of neurons in the nodose ganglia retrogradely labeled from the stomach wall expressed low to moderate VR1 immunoreactivity (VR1-IR). VR1-IR was considerably lower in the nodose ganglia as compared to the jugular and dorsal root ganglia. In the vagus nerve, strongly VR1-IR fibers ran in separate fascicles that supplied mainly cervical and thoracic targets, leaving only weakly VR1-IR fibers in the subdiaphragmatic portion. Vagal afferent intraganglionic laminar endings (IGLEs) in the gastric and duodenal myenteric plexus did not express VR1-IR. Similarly, VR1-IR was contained in fibers running in perfect register with vagal afferents, but was not colocalized with horseradish peroxidase in the same varicosities of intramuscular arrays (IMAs) and vagal afferent fibers in the duodenal submucosa anterogradely labeled from the nodose ganglia. Only in the gastric mucosa did we find evidence for colocalization of VR1-IR in vagal afferent terminals. In contrast, many nerve fibers coursing through the myenteric and submucosal plexuses contained detectable VR1-IR, the majority of which colocalized calcitonin gene-related peptide immunoreactivity. In the dorsal medulla there was a dense plexus of VR1-IR varicose fibers in the commissural, dorsomedial and gelatinosus subnuclei of the medial NTS and the lateral aspects of the area postrema, which was substantially reduced, but not eliminated on the ipsilateral side after supranodose vagotomy. It is concluded that about half of the vagal afferents innervating the gastrointestinal tract express low levels of VR1-IR, but that presence in most of the peripheral terminal structures is below the immunohistochemical detection threshold.

Meal-Induced Hormone Responses in a Rat Model of Roux-en-Y Gastric Bypass Surgery

Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for morbid obesity and remission of associated type 2 diabetes, but the mechanisms involved are poorly understood. The aim of the present study was to develop and validate a rat model for RYGB surgery that allows repeated measurement of meal-induced changes in gut and pancreatic hormones via chronic venous catheters. Male Sprague Dawley rats made obese on a palatable high-fat diet were subjected to RYGB or sham surgery and compared with chow-fed, lean controls. Hormonal responses to a mixed-liquid test meal were examined by frequent blood sampling through chronically implanted jugular catheters in freely behaving rats, 3-4 months after surgery, when RYGB rats had significantly reduced body weight and fat mass compared with sham-operated rats. Hyperleptinemia, basal hyperinsulinemia, and hyperglycemia as well as postprandial glucose intolerance seen in sham-operated, obese rats were completely reversed by RYGB and no longer different from lean controls. Postprandial increases in glucagon-like peptide-1, peptide YY, and amylin as well as suppression of ghrelin levels were all significantly augmented in RYGB rats compared with both sham-operated obese and lean control rats. Thus, our rat model replicates most of the salient hormonal and glycemic changes reported in obese patients after RYGB, with the addition of amylin to the list of potential candidate hormones involved in hypophagia, weight loss, and remission of diabetes. The model will be useful for elucidating the specific peripheral and central mechanisms involved in the suppression of appetite, loss of body weight, and remission of type 2 diabetes.

An expanded view of energy homeostasis: Neural integration of metabolic, cognitive, and emotional drives to eat

The traditional view of neural regulation of body energy homeostasis focuses on internal feedback signals integrated in the hypothalamus and brainstem and in turn leading to balanced activation of behavioral, autonomic, and endocrine effector pathways leading to changes in food intake and energy expenditure. Recent observations have demonstrated that many of these internal signals encoding energy status have much wider effects on the brain, particularly sensory and cortico-limbic systems that process information from the outside world by detecting and interpreting food cues, forming, storing, and recalling representations of experience with food, and assigning hedonic and motivational value to conditioned and unconditioned food stimuli. Thus, part of the metabolic feedback from the internal milieu regulates food intake and energy balance by acting on extrahypothalamic structures, leading to an expanded view of neural control of energy homeostasis taking into account the need to adapt to changing conditions in the environment. The realization that metabolic signals act directly on these non-traditional targets of body energy homeostasis brings opportunities for novel drug targets for the fight against obesity and eating disorders.

Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function.

Orexin‐expressing neurons in the hypothalamus project throughout the neuraxis and are involved in regulation of the sleep/wake cycle, food intake, and autonomic functions. Here we specifically analyze the anatomical organization of orexin projections to the dorsal vagal complex (DVC) and raphé pallidus and effects on ingestive behavior and autonomic functions of local orexin‐A administration in nonanesthetized rats. Retrograde tracing experiments revealed that as many as 20% of hypothalamic orexin neurons project to the DVC, where they form straight varicose axon profiles, some of which are in close anatomical apposition with tyrosine hydroxylase (TH)‐, glucagon‐like peptide‐1‐, γ‐aminobutyric acid‐, and nitric oxide synthase‐immunoreactive neurons in a nonselective manner. Similar contacts were frequently observed with neurons of the nucleus of the solitary tract whose activation by gastrointestinal food stimuli was demonstrated by the expression of nuclear c‐Fos immunoreactivity. Orexin‐A administration to the fourth ventricle induced significant Fos‐expression throughout the DVC compared with saline control injections, with about 20–25% of TH‐ir neurons among the stimulated ones. Fourth ventricular orexin injections also significantly stimulated chow and water intake in nonfood‐deprived rats. Direct bilateral injections of orexin into the DVC increased intake of palatable high‐fat pellets. Orexin‐ir fibers also innervated raphé pallidus. Fourth ventricular orexin‐A (1 nmol) activated Fos expression in the raphé pallidus and C1/A1 catecholaminergic neurons in the ventral medulla and increased body temperature, heart rate, and locomotor activity. The results confirm that hypothalamomedullary orexin projections are involved in a variety of physiological functions, including ingestive behavior and sympathetic outflow. J. Comp. Neurol. 485:127–142, 2005.

Roux-en-Y gastric bypass surgery changes food reward in rats

Context:Roux-en-Y gastric bypass surgery (RYGB) is currently the most effective treatment for morbid obesity, and clinical studies suggest that RYGB patients change food preferences and the desire to eat.Objective:To examine hedonic reactions to palatable foods and food choice behavior in an established rat model of RYGB.Methods and Design:Male Sprague–Dawley (SD) rats and selected line obesity-prone rats that were rendered obese on a high-fat diet underwent RYGB or sham surgery and were tested for ‘liking’ and ‘wanting’ of palatable foods at different caloric densities 4–6 months after surgery.Results:Compared with sham-operated (obese) and age-matched lean control rats, RYGB rats of both models exhibited more positive orofacial responses to low concentrations of sucrose but fewer to high concentrations. These changes in ‘liking’ by RYGB rats were translated into a shift of the concentration–response curve in the brief access test, with more vigorous licking of low concentrations of sucrose and corn oil, but less licking of the highest concentrations. The changes in hedonic evaluation also resulted in lower long-term preference/acceptance of high-fat diets compared with sham-operated (obese) rats. Furthermore, the reduced ‘wanting’ of a palatable reward in the incentive runway seen in sham-operated obese SD rats was fully restored after RYGB to the level found in lean control rats.Conclusions:The results suggest that RYGB leads to a shift in hedonic evaluation, favoring low over high calorie foods and restores obesity-induced alterations in ‘liking’ and ‘wanting’. It remains to be determined whether these effects are simply due to weight loss or specific changes in gut–brain communication. Given the emerging evidence for modulation of cortico-limbic brain structures involved in reward mechanisms by gut hormones, RYGB-induced changes in the secretion of these hormones could potentially be mediating these effects.

Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size

Ingestive behavior is controlled by a complex interplay between signals conveying availability of (1) potentially ingestible food in the environment, (2) digestible food in the alimentary canal, (3) circulating fuels and (4) stored fuels. Each of these four classes of signals interact with specific sensors and neural circuits whose integrated output determines when food intake is initiated and when it is stopped. Because the final common path responsible for oromotor control is contained within complex neural pattern generators within the brainstem and is intimately linked to sensory information from the alimentary canal, at least part of the integration between the four classes of signals is thought to take place at the level of the caudal brainstem. Here we show that CCK, representing a class 2, or direct signal, and MC4-melanocortin receptor activity, representing a second order class 3/4, or indirect signal, converge in the nucleus of the solitary tract where they modulate activity of the mitogen-activated, extracellular-signal regulated kinases 1 and 2 (ERK) pathway to determine the level of satiation. Blockade of this signaling pathway attenuates suppression of deprivation-induced food intake by intraperitoneal CCK and fourth ventricular MTII injection. Additional findings suggest that specific ERK-phosphorylation sites on ion channels and enzymes involved in catecholamine synthesis of NTS neurons may be involved in ERK-mediated satiation and meal termination. Longer-term downstream effects of ERK activation might involve CREB-mediated gene transcription known to produce plasticity changes in neurocircuitry that could determine inter-meal intervals and the size of future meals.

Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation

Orexin-expressing neurons in the lateral hypothalamus with their wide projections throughout the brain are important for the regulation of sleep and wakefulness, ingestive behavior, and the coordination of these behaviors in the environmental context. To further identify downstream effector targets of the orexin system, we examined in detail orexin-A innervation of the caudal raphé nuclei in the medulla, known to harbor sympathetic preganglionic motor neurons involved in thermal, cardiovascular, and gastrointestinal regulation. All three components of the caudal raphé nuclei, raphé pallidus, raphé obscurus, and parapyramidal nucleus, are innervated by orexin-A-immunoreactive fibers. Using confocal microscopy, we demonstrate close anatomical appositions between varicose orexin-A immunoreactive axon profiles and sympathetic premotor neurons identified with either a transneuronal retrograde pseudorabies virus tracer injected into the interscapular brown fat pads, or with in situ hybridization of pro-TRH mRNA. Furthermore, orexin-A injected into the fourth ventricle induced c-Fos expression in the raphé pallidus and parapyramidal nucleus. These findings suggest that orexin neurons in the hypothalamus can modulate brown fat thermogenesis, cardiovascular, and gastrointestinal functions by acting directly on neurons in the caudal raphé nuclei, and support the idea that orexin’s simultaneous stimulation of food intake and sympathetic activity might have evolved as a mechanism to stay alert while foraging.

Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats.

Background  Roux‐en‐Y gastric bypass (RYGB) surgery is very effective in reducing excess body weight and improving glucose homeostasis in obese subjects. Changes in the pattern of gut hormone secretion are thought to play a major role, but the mechanisms leading to both changed hormone secretion and beneficial effects remain unclear. Specifically, it is not clear whether changes in the number of hormone‐secreting enteroendocrine cells, or changes in the releasing stimuli, or both, are important.