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

Abstract

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 foodrelated 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.functional MRI ͉ obesity ͉ hunger ͉ prefrontal cortex ͉ insula L eptin, the primary signaling hormone from adipocyte energy stores, regulates feeding behavior and energy expenditure (1). A recessive missense mutation (c313CϾT Arg105Trp) in the ob gene was identified in three adults (two women and one man) and one child from a family in Turkey (2). The only other known mutation producing congenital leptin deficiency is a frame shift/premature stop (c398delG ⌬133G), identified in three families of Pakistani origin (3). Before treatment with leptin supplement was initiated, the adults with the Arg105Trp mutation were morbidly obese and hypogonadal, and one of them had type-2 diabetes mellitus. Concomitant with weight loss, replacement of leptin to the adults with the Arg105Trp mutation normalized endocrine and other health measures (4) and produced a 50% reduction in food intake (during the first 15 weeks) that correlated with ratings of hunger and desire to eat (5). Moreover, supplementation was associated with sustained increases in brain gray matter concentration in the anterior cingulate gyrus, inferior parietal lobule, and cerebellum (6). Leptin treatment had similar effects on body weight and health measures for patients identified with the ⌬133G mutation (7) as well as mice that bear a homologous gene mutation (ob/ob mice) (8).Consistent with a direct action in the brain, leptin receptors are found in the cerebral cortex, hippocampus, basal ganglia, hypothalamus, brainstem, and cerebellum (9). However, the neural circuits through which leptin alters human feeding behavior are not known. We addressed this question by pairing functional magnetic resonance imaging (fMRI) with presentation of food images to the three leptin-deficient adults with the Arg105Trp mutation with and without leptin treatment. In healthy adults, presentation of food increases ratings of hunger and cerebral glucose metabolism, particularly in the orbitofrontal cortex, somatosensory cortex, superior temporal cortex, occipital cortex, insula, basal ganglia, and thalamus (10); images of high-calorie foods increase ratings of hunger and activate a network of brain regions, including the medial and dorsolateral prefrontal cortex (PFC), corpus callosum, amygdala, thalamus, hypothalamus, and cerebellum (11). We hypothesized that leptin replacement wo...

Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: Possible contributing factors

“…Imaging studies reported activation of the somatosensory cortex in normal weight subjects with exposure to visual images of low caloric foods (Killgore et al, 2003) and with satiety (Tataranni et al, 1999), and we had shown higher than normal baseline metabolism in the somatosensory cortex in obese subjects (Wang et al, 2002). Also a recent study reported that in obese individuals with leptin deficiency administration of leptin normalized their body weight and reduced brain activation in parietal cortex while viewing food-related stimuli (Baicy et al, 2007). The functional connectivity between the striatum and the somatosensory cortex was recently corroborated for the human brain by a meta-analysis study on 126 functional imaging studies, which documented coactivation of the somatosensory cortex with that of the dorsal striatum (Postuma and Dagher, 2006).…”

Differences in response to food stimuli in a rat model of obesity: in-vivo assessment of brain glucose metabolism

“…Therefore, there is increasing evidence of importance of leptin in processing food stimuli. 21 Evidence of hippocampal involvement in food-related behaviors has also been reported. To start with, the neuroanatomical connections of the hippocampus allow it to receive information from areas of the brain involved in satiety and hunger signals including the arcuate nucleus in the hypothalamus, 22 the nucleus tractus solitarius, which receives afferents from the vagus 23 that are thought to regulate food intake 24 and from the insula, which processes internal perception of hunger signals 25 and in concert with the hippocampus is thought to be involved in novel taste learning.…”

Brain Activation by Visual Food-Related Stimuli and Correlations with Metabolic and Hormonal Parameters: A fMRI Study

“…One of the most important adipokines, leptin, has been implicated in a variety of functions of the central nervous system such as learning and memory processes, neuroendocrine regulation, and possibly neuroprotection [17][18][19][20]. Leptin replacement in genetically leptin-deficient adults modulates the sensitivity to visual food stimuli, with reduced activation in hunger related areas and enhanced response in regions involved in satiation [21,22]. Likewise, metabolic factors such as glucose and free fatty acids (FFA) are likely to serve as regional modulators of postprandial neuronal events [23].…”