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

Abstract

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...

Leptin alters energy intake and fat mass but not energy expenditure in lean subjects

“…Regarding energy intake, in ob/ob mice and lean rodents, leptin replacement decreases caloric intake 9 , 37 , 56 . Similarly, in severe hypoleptinemic populations with CLD or GL, leptin decreases robust food intake by affecting hedonic and homeostatic nervous centers that control satiety and hunger feeling 31 , 57 , 58 . In lean women with mild acquired hypoleptinemia, leptin administration reduces salience, attention, and rewarding value of food 59 .…”

Intranasal insulin enhances brain functional connectivity mediating the relationship between adiposity and subjective feeling of hunger

“…In the fasting compared to the fed state 46 hypothalamic-PFC functional connectivity was enhanced, while the ingestion of a meal reduced functional connectivity to the medial and lateral PFC 45, 47 . Interestingly, other hormonal interventions with leptin 48, 49 or intranasal oxytocin 50–52 have likewise shown to alter PFC functional connectivity. Leptin replacement therapy in patients with lipodystrophy, for example, significantly increased hypothalamic-PFC functional connectivity accompanied by normalization of eating behavior 49 .…”

“…Interestingly, other hormonal interventions with leptin 48, 49 or intranasal oxytocin 50–52 have likewise shown to alter PFC functional connectivity. Leptin replacement therapy in patients with lipodystrophy, for example, significantly increased hypothalamic-PFC functional connectivity accompanied by normalization of eating behavior 49 . Accordingly, in the current study we found the functional connection between the anterior medial PFC and the hypothalamus to increase in participants with favorable peripheral insulin sensitivity.…”

Diagnosis and treatment of lipodystrophy: a step-by-step approach

“…Paired biopsy studies have shown that nonalcoholic steatohepatitis associated with GLD was ameliorated with metreleptin treatment [ 75 , 76 ]. During 52 weeks of metreleptin treatment, improved brain connectivity associated with hedonic and homeostatic control of eating behavior, decreased hunger, and increased satiety were observed [ 77 ].…”