Functional Magnetic Resonance Imaging Analysis of Food-Related Brain Activity in Patients with Lipodystrophy Undergoing Leptin Replacement Therapy

Aotani, Daisuke; Ebihara, Ken; Sawamoto, Nobukatsu; Kusakabe, Toru; Aizawa-Abe, Megumi; Kataoka, Satoshi; Sakai, Toshiyasu; Iogawa, Hitomi; Ebihara, Chihiro; Fujikura, Junji; Hosoda, Kiminori; Fukuyama, Hidenao; Nakao, Kazuwa

doi:10.1210/jc.2012-1872

Cited by 45 publications

(31 citation statements)

References 40 publications

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“…1 has been published so far in metreleptin treatment-naive subjects with leptin-deficiency. Furthermore, the current study is the first to describe metreleptin treatment-associated alterations in resting state connectivity compared with published fMRI studies with eventrelated designs ranging from n = 1 to 3 subjects (33)(34)(35)(36); one study reported on 10 subjects who were not treatment naive (13). A replication of the current fMRI results in larger samples would be valuable.…”

Section: Discussionmentioning

confidence: 74%

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Leptin Substitution in Patients With Lipodystrophy: Neural Correlates for Long-term Success in the Normalization of Eating Behavior

et al. 2016

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Lipodystrophy (LD) is a rare disease with a paucity of subcutaneous adipocytes and leptin deficiency. Patients often develop severe diabetes and, additionally, show a disturbed eating behavior with reduced satiety. The disturbed eating behavior can be restored by substitution with the leptin analog metreleptin. Long-term effects of metreleptin on resting state brain connectivity in treatmentnaive patients with LD have not been assessed. In this study, resting state functional MRI scans and extensive behavioral testing assessing changes in hunger/satiety regulation were performed during the first 52 weeks of metreleptin treatment in nine patients with LD. Resting state connectivity significantly increased over the course of metreleptin treatment in three brain areas (i.e., hypothalamus, insula/superior temporal gyrus, medial prefrontal cortex). Behavioral tests demonstrated that perceived hunger, importance of eating, eating frequencies, and liking ratings of food pictures significantly decreased during metreleptin therapy. Taken together, leptin substitution was accompanied by longterm changes of hedonic and homeostatic central nervous networks regulating eating behavior as well as decreased hunger feelings and diminished incentive value of food. Future studies need to assess whether metreleptin treatment in LD restores physiological processes important for the development of satiety.Lipodystrophy (LD) is a rare disease with a paucity of subcutaneous adipocytes and reduced blood concentrations of leptin. Several genetic mutations are known to cause partial or generalized forms of the disease. Also, cases of acquired LD have occurred (1). LD is frequently accompanied by type 2 diabetes and dyslipidemia. Leptin substitution in the form of the analog metreleptin has shown beneficial metabolic effects. In the biggest clinical trial on metreleptin treatment in LD so far, hemoglobin A 1c (HbA 1c ) on average decreased by 1.5% and serum triglycerides (TGs) fell by .50% after 1 year of treatment (2). Additionally, a disturbed eating behavior often develops in patients with LD, with reduced satiety after food consumption, leading to an increase in meal frequency (3). Impaired eating behavior can be improved by leptin substitution, too (4). Humoral leptin crosses the blood-brain barrier by active transport in the proximity of the mediobasal hypothalamus where the blood-brain barrier is well permeable for peripheral hormones (3,5). Through receptors in the arcuate nucleus, leptin inhibits food intake by direct activation of anorexigenic cocaine-and amphetamine-regulated transcript and proopiomelanocortin neurons (6,7) as well as by inhibition of orexigenic neuropeptide Y neurons (8). In a widely accepted model of the control of eating behavior, the hypothalamus is considered to govern the homeostatic component of human eating regulation, that is, the drive to eat to meet the bodily demands for energy (9,10).In addition, the leptin receptor is also expressed in neurons of the mesolimbic dopamine system, which is involved in...

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Section: Discussionmentioning

confidence: 74%

“…These findings also suggest an influence of leptin on the other component contributing to the formation of human eating behavior, that is, hedonic eating, which is the drive to eat for pleasure in the absence of an energy deficit (12). Human behavioral data support the hypothesis that leptin affects both components of eating control (4,13).…”

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confidence: 61%

Leptin Substitution in Patients With Lipodystrophy: Neural Correlates for Long-term Success in the Normalization of Eating Behavior

et al. 2016

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“…However, dual X-ray absorptiometry analysis failed to reveal a significant increase in fat mass upon rosiglitazone treatment, likely due to a lack of sensitivity of the method. This raises the question of the presence of remaining fat pads in BSCL patients, although the presence of WAT in BSCL2 patients has been detected by different techniques (dual energy X-ray densitometry or magnetic resonance imaging) [31,32]. Actually, recombinant leptin injection is the gold-standard therapy in adults [33,34] and children [35] with BSCL.…”

Section: Discussionmentioning

confidence: 99%

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Prieur¹,

Dollet²,

Takahashi³

et al. 2013

Diabetologia

136

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Aims/hypothesis Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Methods Bscl2−/− mice were generated and phenotyped. X. Prieur, L. Dollet and M. Takahashi contributed equally to this study.Electronic supplementary material The online version of this article

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“…Using functional MRI, Aotani et al [41] have recently shown that leptin therapy helps to suppress postprandial neuronal activity in certain brain areas, which can lead to improved satiety. All this clearly suggests that leptin has a strong influence on the central regulation of feeding, and this might be an important contributor to its metabolic effects.…”

Section: Mechanisms Of Leptin Actionmentioning

confidence: 99%

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

Simha

2014

Expert Review of Endocrinology & Metabolism

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Lipodystrophy is a group of acquired and inherited disorders characterized by selective loss of adipose tissue. Despite wide genotypic and phenotypic variety, many patients with lipodystrophy have similar metabolic complications including insulin resistance, diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Often, these metabolic abnormalities are severe and difficult to treat with conventional glucose and lipid-lowering therapies. Lack of adipose tissue also results in marked hypoleptinemia, and there has recently been much interest in using leptin-replacement therapy to treat the metabolic complications of lipodystrophy. Administration of metreleptin, the human recombinant leptin analogue, has been shown in prospective, open-label studies to improve glucose control, dyslipidemia and steatohepatitis. This article summarizes the current evidence for the safety and efficacy of leptin-replacement therapy in patients with lipodystrophy.

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Functional Magnetic Resonance Imaging Analysis of Food-Related Brain Activity in Patients with Lipodystrophy Undergoing Leptin Replacement Therapy

Cited by 45 publications

References 40 publications

Leptin Substitution in Patients With Lipodystrophy: Neural Correlates for Long-term Success in the Normalization of Eating Behavior

Leptin Substitution in Patients With Lipodystrophy: Neural Correlates for Long-term Success in the Normalization of Eating Behavior

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

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