Leptin Therapy Alters Appetite and Neural Responses to Food Stimuli in Brain Areas of Leptin-Sensitive Subjects Without Altering Brain Structure

Farr, Olivia M.; Fiorenza, Christina G.; Papageorgiou, Panagiotis; Brinkoetter, Mary; Ziemke, Florencia; Koo, Bang‐Bon; Rojas, Rafael; Mantzoros, Christos S.

doi:10.1210/jc.2014-2774

Cited by 37 publications

(26 citation statements)

References 52 publications

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“…The fMRI protocol consisted of five runs, during which subjects viewed blocks of highly desirable (high-calorie or high-fat images such as cakes, onion rings, and other similar foods), less desirable (low-calorie or low-fat images such as vegetables and fruits), or nonfood images (examples included flowers, rocks, and trees) and provided responses on how well they could imagine or visualize each image using a response box held in their right hand, as previously described (19,20). Approximately 150 images were used in randomized order, presented during both the fasting and fed states.…”

Section: Methodsmentioning

confidence: 99%

“…On the basis of an a priori hypothesis for the hypothalamus, owing to findings in rodents of lorcaserin’s weight-reducing efficacy being mediated by the hypothalamus, we performed a region of interest analysis for the hypothalamus using a 10-mm radius sphere, as defined previously (19). Effect size data for hypothalamus and for activations, which were significantly different for week 1 > week 0 and for week 1 > week 4, contrasts were extracted using MarsBaR (http://marsbar.sourceforge.net/).…”

Section: Methodsmentioning

confidence: 99%

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Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial

et al. 2016

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Lorcaserin is a serotonin 5-hydroxytryptamine 2c receptor agonist effective in treating obesity. Studies in rodents have shown that lorcaserin acts in the brain to exert its weight-reducing effects, but this has not yet been studied in humans. We performed a randomized, placebo-controlled, double-blind trial with 48 obese participants and used functional MRI to study the effects of lorcaserin on the brain. Subjects taking lorcaserin had decreased brain activations in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state. Decreases in emotion- and salience-related limbic activity, including the insula and amygdala, were attenuated at 4 weeks. Decreases in caloric intake, weight, and BMI correlated with activations in the amygdala, parietal, and visual cortices at baseline. These data suggest that lorcaserin exerts its weight-reducing effects by decreasing attention-related brain activations to food cues (parietal and visual cortices) and emotional and limbic activity (insula, amygdala). Results indicating that baseline activation of the amygdala relates to increased efficacy suggest that lorcaserin would be of particular benefit to emotional eaters.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial

et al. 2016

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“…These can all be restored to normal levels with leptin replacement therapy [10,12,15,41]. Most recently, we showed that three hypoleptinemic women with HA had no structural brain differences from healthy controls and/or in response to leptin treatment [42*]. However, these hypoleptinemic women showed enhanced activations to food cues in areas related to salience and reward after short-term (1 week) therapy, and decreased activations to food cues in areas involved in attention and reward after long-term (6 months) treatment [42*].…”

Section: Leptin Deficiencymentioning

confidence: 99%

“…Most recently, we showed that three hypoleptinemic women with HA had no structural brain differences from healthy controls and/or in response to leptin treatment [42*]. However, these hypoleptinemic women showed enhanced activations to food cues in areas related to salience and reward after short-term (1 week) therapy, and decreased activations to food cues in areas involved in attention and reward after long-term (6 months) treatment [42*]. Although similar to congenital leptin deficiency, these women had normal levels of leptin during development, which may account for differences in gray matter volume or brain size changes.…”

Section: Leptin Deficiencymentioning

confidence: 99%

Leptin applications in 2015

Farr

Gavrieli

Mantzoros³

2015

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review To summarize previous and current advancements for leptin therapeutics, we described how leptin may be useful in leptin deficient states such as lipodystrophy, for which leptin was recently approved, and how it may be useful in the future for typical obesity. Recent findings The discovery of leptin in 1994 built the foundation for understanding the pathophysiology and treatment of obesity. Leptin therapy reverses morbid obesity related to congenital leptin deficiency and appears to effectively treat lipodystrophy, a finding which has led to the approval of leptin for the treatment of lipodystrophy in the USA and Japan. Typical obesity, on the other hand, is characterized by hyperleptinemia and leptin resistance. Thus, leptin administration has proven ineffective for inducing weight loss on its own but may be useful in combination with other therapies or for weight loss maintenance. Summary Leptin is not yet able to treat typical obesity, however, it is effective for reversing leptin deficiency-induced obesity and lipodystrophy. New mechanisms and pathways involved in leptin resistance are continuously discovered, while the development of new techniques and drug combinations which may improve leptin’s efficacy and safety regenerate the hope for its use as an effective treatment for typical obesity.

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“…Enterohormonal signals may also mediate how the brain responds to food cues, providing an indirect mechanism for central actions of GLP-1 agonists [8–11]. We have recently shown decreased attention-related parietal cortex activations to highly desirable food cues during a fasting-state fMRI study with a short course of liraglutide, pointing to a central mechanism of action [12].…”

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confidence: 99%

Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study

et al. 2016

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Background GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics. Basic Procedures Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17 days (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days) of treatment, we also studied changes in fMRI responses to food cues. Main Findings By design, to avoid any confounding by weight changes, subjects were studied for 17 days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA. Principal Conclusions We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that would over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.

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Leptin Therapy Alters Appetite and Neural Responses to Food Stimuli in Brain Areas of Leptin-Sensitive Subjects Without Altering Brain Structure

Abstract: Leptin replacement in acutely hypoleptinemic women did not alter brain structure but did alter functional cortical activity to food cues in key feeding and reward-related areas.

Cited by 37 publications

References 52 publications

Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial

Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial

Leptin applications in 2015

Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study

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