Leptin replacement alters brain response to food cues in genetically leptin-deficient adults

Department of Psychiatry and Biobehavioral Sciences and Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90024, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2007; 104(46):18276-9. DOI: 10.1073/pnas.0706481104
Source: PubMed


A missense mutation in the ob gene causes leptin deficiency and morbid obesity. Leptin replacement to three adults with this mutation normalized body weight and eating behavior. Because the neural circuits mediating these changes were unknown, we paired functional magnetic resonance imaging (fMRI) with presentation of food cues to these subjects. During viewing of food-related stimuli, leptin replacement reduced brain activation in regions linked to hunger (insula, parietal and temporal cortex) while enhancing activation in regions linked to inhibition and satiety (prefrontal cortex). Leptin appears to modulate feeding behavior through these circuits, suggesting therapeutic targets for human obesity.

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Available from: Edythe D London
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    • "Both are compulsive behavioral disorders that can be viewed as stemming from maladaptive plasticity in the mesolimbic dopaminergic (DA) system, which is essential for the development of adaptive motivated behaviors (Volkow et al., 2013). In this review, we will describe how regulation of food intake by the hypothalamus can be modulated by the neurocircuitry for reward and motivation (Baicy et al., 2007; Farooqi et al., 2007) (Fig. 1). The neural circuit of homeostatic regulation of feeding has been discussed in many excellent reviews (Morton et al., 2006; Morton and Salovitz, 2006; Sternson, 2013; Morton et al., 2014). "
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    ABSTRACT: Hunger, mostly initiated by a deficiency in energy, induces food seeking and intake. However, the drive toward food is not only regulated by physiological needs, but is motivated by the pleasure derived from ingestion of food, in particular palatable foods. Therefore, feeding is viewed as an adaptive motivated behavior that involves integrated communication between homeostatic feeding circuits and reward circuits. The initiation and termination of a feeding episode are instructed by a variety of neuronal signals, and maladaptive plasticity in almost any component of the network may lead to the development of pathological eating disorders. In this review we will summarize the latest understanding of how the feeding circuits and reward circuits in the brain interact. We will emphasize communication between the hypothalamus and the mesolimbic dopamine system and highlight complexities, discrepancies, open questions and future directions for the field.
    Full-text · Article · Apr 2015
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    • "Increasing evidence indicates that homeostatic regulators of food intake, such as leptin, insulin, and ghrelin, control and interact with the reward circuit of food intake, and thus regulate behavioral aspects of food intake and conditioning to food stimuli behaviors (Abizaid et al., 2006; Fulton et al., 2006; Hommel et al., 2006; Baicy et al., 2007; Farooqi et al., 2007; Palmiter, 2007; Konner et al., 2011; Volkow et al., 2011). Recent findings reveal that hormones implicated in regulating energy homeostasis also impinge directly on DA neurons; for example, leptin and insulin directly inhibit DA neurons, while ghrelin activates them (Palmiter, 2007; Kenny, 2011). "
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    ABSTRACT: Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.
    Full-text · Article · Oct 2013 · Frontiers in Neural Circuits
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    • "Consequently, different authors investigated the neuronal networks that responded to specific orexigenic or anorexigenic signals (Batterham et al., 2007; Miller et al., 2007; Malik et al., 2008). Currently, the applications of BOLD fMRI on studies of appetite regulation are mainly dedicated to the study of hypothalamic response to glucose (Vidarsdottir et al., 2007; Purnell et al., 2011), to the establishment of differences between fMRI responses in obese and non-obese humans (Tomasi et al., 2009), and to the effects of appetite modulating hormones derived from the gastrointestinal tract and adipose tissue, mainly ghrelin (Jones et al., 2012), insulin (Guthoff et al., 2010) and leptin (Baicy et al., 2007; Farooqi et al., 2007). Figure 4 illustrates a representative application of BOLD imaging to appetite regulation in a study that monitored hypothalamic activation in humans, as induced by a paradigm that showed images of high-and low-calorie foods. "
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    ABSTRACT: We review the role of neuroglial compartmentation and transcellular neurotransmitter cycling during hypothalamic appetite regulation as detected by Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) methods. We address first the neurochemical basis of neuroendocrine regulation in the hypothalamus and the orexigenic and anorexigenic feed-back loops that control appetite. Then we examine the main MRI and MRS strategies that have been used to investigate appetite regulation. Manganese-enhanced magnetic resonance imaging (MEMRI), Blood oxygenation level-dependent contrast (BOLD), and Diffusion-weighted magnetic resonance imaging (DWI) have revealed Mn(2+) accumulations, augmented oxygen consumptions, and astrocytic swelling in the hypothalamus under fasting conditions, respectively. High field (1)H magnetic resonance in vivo, showed increased hypothalamic myo-inositol concentrations as compared to other cerebral structures. (1)H and (13)C high resolution magic angle spinning (HRMAS) revealed increased neuroglial oxidative and glycolytic metabolism, as well as increased hypothalamic glutamatergic and GABAergic neurotransmissions under orexigenic stimulation. We propose here an integrative interpretation of all these findings suggesting that the neuroendocrine regulation of appetite is supported by important ionic and metabolic transcellular fluxes which begin at the tripartite orexigenic clefts and become extended spatially in the hypothalamus through astrocytic networks becoming eventually MRI and MRS detectable.
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