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Christos S Mantzoros - One of the best experts on this subject based on the ideXlab platform.

  • Circulating levels of the components of the GH/IGF-1/IGFBPs axis total and intact IGF-binding proteins (IGFBP) 3 and IGFBP 4 and total IGFBP 5, as well as PAPPA, PAPPA2 and Stanniocalcin-2 levels are not altered in response to energy deprivation and/
    Metabolism: clinical and experimental, 2019
    Co-Authors: Eleni Pilitsi, Natia Peradze, Nikolaos Perakakis, Christos S Mantzoros
    Abstract:

    Abstract Objective It remains unclear whether food deprivation induces changes in components of the GH/IGF-1/IGFBPs axis and if yes, which ones are mediated by leptin, an adipocyte secreted hormone regulating neuroendocrine response to energy deprivation in animals and humans. We aimed to investigate components of the axis that have not been studied to date, i.e. IGF-binding proteins (IGFBPs) and related proteases (total and intact IGFBP 3 and IGFBP 4, total IGFBP 5, PAPPA, PAPPA2 and Stanniocalcin-2), during acute (short-term fasting in healthy subjects) and chronic (women with hypothalamic amenorrhea [HA] due to excessive exercise) energy deprivation and whether Metreleptin administration, in replacement, supraphysiologic or pharmacologic levels, may mediate any changes of circulating levels of the above molecules in healthy individuals and in women with hypothalamic amenorrhea. Methods We studied: 1) 11 healthy men and women during three four day admissions i.e. a baseline admission in the fed isocaloric state and two admissions in the complete food deprivation state for 72-h with either placebo (resulting in a hypoleptinemic state) or Metreleptin administration in doses designed to normalize circulating leptin levels for the duration of the study, 2) 15 healthy men and women during three 72-hour long admissions in a complete food deprivation state receiving three escalating doses of Metreleptin designed to bring circulating leptin levels to physiologic, supraphysiologic, or pharmacologic levels, and 3) 18 women with HA randomized to either Metreleptin treatment in replacement doses or placebo for nine months. Results There were no significant changes in the circulating profiles of the above molecules in the fasting vs. fed state and/or with Metreleptin administration during acute and chronic energy deprivation. Conclusions The studied components of the GH/IGF-1/IGFBPs axis are not affected by energy deprivation, leptin deficiency associated with energy deprivation, or by Metreleptin administration in physiologic, supraphysiologic or pharmacologic doses.

  • identification and saturable nature of signaling pathways induced by Metreleptin in humans comparative evaluation of in vivo ex vivo and in vitro administration
    Diabetes, 2015
    Co-Authors: Hyun Seuk Moon, Joo Young Huh, Fadime Dincer, Benjamin E Schneider, Perolof Hasselgren, Christos S Mantzoros
    Abstract:

    Signaling pathways activated by leptin in metabolically important organs have largely been studied only in animal and/or cell culture studies. In this study, we examined whether leptin has similar effects in human peripheral tissues in vivo, ex vivo, and in vitro and whether the response would be different in lean and obese humans. For in vivo leptin signaling, Metreleptin was administered and muscle, adipose tissue, and peripheral blood mononuclear cells were taken for analysis of signal activation. Experiments were also done ex vivo and with primary cultured cells in vitro. The signal activation was compared between male versus female and obese versus lean humans. Acute in vivo, ex vivo, and/or in vitro Metreleptin administration similarly activated STAT3, AMPK, ERK1/2, Akt, mTOR, NF-κB, and/or IKKα/β without any differences between male versus female and obese versus lean subjects. All signaling pathways were saturable at ∼30–50 ng/mL, consistent with the clinical evidence showing no additional effect(s) in obese subjects who already have high levels of leptin. Our data provide novel information on downstream effectors of Metreleptin action in humans that may have therapeutic implications.

  • leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin sensitive subjects without altering brain structure
    The Journal of Clinical Endocrinology and Metabolism, 2014
    Co-Authors: Olivia M Farr, Mary Brinkoetter, Christina G. Fiorenza, Panagiotis Papageorgiou, Florencia Ziemke, Bangbon Koo, Rafael Rojas, Christos S Mantzoros
    Abstract:

    Context: Leptin is a key regulator of energy intake and expenditure. Individuals with congenital leptin deficiency demonstrate structural and functional brain changes when given leptin. However, whether acquired leptin deficiency may operate similarly is unclear. Objective: We set out to determine whether the brains of individuals with acquired leptin deficiency may react to leptin in a similar manner. Design: We used functional magnetic resonance imaging before and after short- and long-term Metreleptin treatment in three leptin-sensitive patients with acquired hypoleptinemia. Nine healthy women were scanned as normoleptinemic controls. Setting: The setting was an academic medical center. Patients or Other Participants: The participants were 3 hypoleptinemic women and nine normoleptinemic, matched women. Interventions: We used Metreleptin, recombinant leptin, therapy for 24 weeks in hypoleptinemic women only. Main Outcome Measure: We measured neural changes in response to viewing food as compared to nonf...

  • the effect of leptin replacement on parathyroid hormone rankl osteoprotegerin axis and wnt inhibitors in young women with hypothalamic amenorrhea
    The Journal of Clinical Endocrinology and Metabolism, 2014
    Co-Authors: Stergios A Polyzos, Sharon H Chou, Christos S Mantzoros, Athanasios D Anastasilakis
    Abstract:

    Context: Recombinant leptin (Metreleptin) treatment restores bone mineral density in women with hypothalamic amenorrhea (HA), a condition characterized by hypoleptinemia, which has adverse impact on bone health. Objective: The objective of the study was to investigate how Metreleptin exerts its positive effect on bone metabolism in humans. Design: This was a randomized, double-blinded, placebo-controlled study. Setting: The study was conducted at Beth Israel Deaconess Medical Center (Boston, Massachusetts). Patients and Interventions: Women (n = 18) with HA and hypoleptinemia for at least 6 months were randomized to receive either Metreleptin or placebo for 36 weeks. Serum samples were obtained at baseline and 12, 24, and 36 weeks of treatment. Main Outcome Measures: Circulating levels of leptin, intact PTH (iPTH), receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), sclerostin, dickkopf-1, and fibroblast growth factor-23. Results: Metreleptin administration significantly increas...

  • chemerin is expressed mainly in pancreas and liver is regulated by energy deprivation and lacks day night variation in humans
    European Journal of Endocrinology, 2013
    Co-Authors: John P Chamberland, Konstantinos N. Aronis, Reena Berman, Christos S Mantzoros
    Abstract:

    Objective: Chemerin is an adipocyte-secreted hormone and has recently been associated with obesity and the metabolic syndrome. Although studies in rodents have outlined the aspects of chemerin’s function and expression, its physiology and expression patterns are still to be elucidated in humans. Methods: To evaluate for any day/night variation in chemerin secretion, we analyzed hourly serum samples from six females in the fed state. To examine whether energy deprivation affects chemerin levels, and whether this could be mediated through leptin, we analyzed samples from the same subjects in the fasting state while administering either placebo or leptin. To evaluate for any potential dose– effect relationship between leptin and chemerin, we administered increasing Metreleptin doses to five females. A tissue array was used to study the expression of chemerin in different human tissues. Ex vivo treatment of human fat explants from three subjects with leptin was carried out to evaluate for any direct effect of leptin on adipocyte chemerin secretion. Results: Chemerin does not display a day/night variation, while acute energy deprivation resulted in a significant drop in circulating chemerin levels by w42%. The latter was unaltered by Metreleptin administration, and leptin administration did not affect the secretion of chemerin by human adipose tissue studied ex vivo. Chemerin was expressed primarily in the pancreas and liver. Chemerin receptor showed increased expression in the lymph nodes and the spleen. Conclusions: We outline for the first time chemerin expression and physiology in humans, which are different from those in mice.

John P Chamberland - One of the best experts on this subject based on the ideXlab platform.

  • gender dimorphism and lack of day night variation or effects of energy deprivation on undercarboxylated osteocalcin levels in humans
    Obesity, 2013
    Co-Authors: Joo-pin Foo, John P Chamberland, Konstantinos N. Aronis, Ole-petter R. Hamnvik, Bindiya Thakkar, Mary Brinkoetter
    Abstract:

    Objective Undercarboxylated osteocalcin (ucOC) is a bone marker with potent metabolic effects. Leptin regulates Esp gene expression and osteocalcin carboxylation in animal models. We aim to elucidate day/night patterns of ucOC levels, whether short-term and/or chronic energy deprivation alters ucOC levels, and whether leptin may mediate these changes in humans. Design and Methods Twelve healthy males and females were studied for 72 h in the fed state to study day/night pattern of ucOC. The six female subjects were also studied in a crossover interventional study in the fasting state for 72 h with administration of either placebo or Metreleptin in physiological doses. Blood samples were obtained hourly from 0800 a.m. on day 3 until 0800 a.m. on day 4. In a separate study, eleven obese subjects who underwent bariatric surgery were followed for 24 weeks to examine the effects of postsurgery weight loss on ucOC levels. Results Males have higher ucOC levels compared to females. There is no day/night variation pattern of circulating ucOC in humans. Short-term and chronic energy deprivation or leptin administrations do not alter ucOC levels. Conclusions The hypothesis that ucOC plays a role in energy homeostasis or of leptin in regulating ucOC in humans is not supported.

  • chemerin is expressed mainly in pancreas and liver is regulated by energy deprivation and lacks day night variation in humans
    European Journal of Endocrinology, 2013
    Co-Authors: John P Chamberland, Konstantinos N. Aronis, Reena Berman, Christos S Mantzoros
    Abstract:

    Objective: Chemerin is an adipocyte-secreted hormone and has recently been associated with obesity and the metabolic syndrome. Although studies in rodents have outlined the aspects of chemerin’s function and expression, its physiology and expression patterns are still to be elucidated in humans. Methods: To evaluate for any day/night variation in chemerin secretion, we analyzed hourly serum samples from six females in the fed state. To examine whether energy deprivation affects chemerin levels, and whether this could be mediated through leptin, we analyzed samples from the same subjects in the fasting state while administering either placebo or leptin. To evaluate for any potential dose– effect relationship between leptin and chemerin, we administered increasing Metreleptin doses to five females. A tissue array was used to study the expression of chemerin in different human tissues. Ex vivo treatment of human fat explants from three subjects with leptin was carried out to evaluate for any direct effect of leptin on adipocyte chemerin secretion. Results: Chemerin does not display a day/night variation, while acute energy deprivation resulted in a significant drop in circulating chemerin levels by w42%. The latter was unaltered by Metreleptin administration, and leptin administration did not affect the secretion of chemerin by human adipose tissue studied ex vivo. Chemerin was expressed primarily in the pancreas and liver. Chemerin receptor showed increased expression in the lymph nodes and the spleen. Conclusions: We outline for the first time chemerin expression and physiology in humans, which are different from those in mice.

  • fibroblast growth factor 21 levels in young healthy females display day and night variations and are increased in response to short term energy deprivation through a leptin independent pathway
    Diabetes Care, 2013
    Co-Authors: Joo-pin Foo, John P Chamberland, Christos S Mantzoros, Konstantinos N. Aronis, Jason Paruthi, Hyun Seuk Moon
    Abstract:

    OBJECTIVE Fibroblast growth factor (FGF)-21 is an endocrine factor with potent metabolic effects. Its day–night patterns of secretion and/or its physiological response to energy deprivation and relationship to free fatty acids (FFAs) and/or leptin remain to be fully elucidated. We aim to elucidate day–night pattern of FGF-21 levels and its relationship to FFA, to assess whether energy deprivation alters its circulating patterns, and to examine whether leptin may mediate these changes. RESEARCH DESIGN AND METHODS Six healthy lean females were studied for 72 h in a cross-over interventional study under three different conditions: on isocaloric diet and in a fasting state with administration of either placebo or Metreleptin in physiological replacement doses. Blood samples were obtained hourly from 8:00 a.m. on day 4 until 8:00 a.m. on day 5. RESULTS FGF-21 exhibited day–night variation pattern during the isocaloric fed state. Fasting significantly increased FGF-21 levels ( P CONCLUSIONS A day–night variation in the levels of FGF-21 exists in young lean females in the fed state. Energy deprivation increases FGF-21 levels via a leptin-independent pathway. The interaction between FGF-21 and starvation-induced lipolysis, as indicated by its close cross-correlations with FFA in both fed state and energy deprivation, needs to be studied further.

  • short term energy deprivation alters activin a and follistatin but not inhibin b levels of lean healthy women in a leptin independent manner
    The Journal of Clinical Endocrinology and Metabolism, 2011
    Co-Authors: Vasiliki A Moragianni, John P Chamberland, Christos S Mantzoros, Konstantinos N. Aronis
    Abstract:

    Context: Leptin is a potent modulator of the hypothalamic-pituitary-gonadal axis mediating the effect of energy deprivation on several hypothalamic-pituitary-peripheral axes. Activin A, inhibin B, and follistatin (FST) also regulate the hypothalamic-pituitary-gonadal axis in humans. It remains unknown whether energy deprivation affects these hormone levels in a leptin-dependent or -independent manner. Objective: We investigated 1) day-night variability patterns of activin, inhibin, and FST in the fed state, 2) whether their levels are affected by fasting, and 3) whether such an effect is mediated by leptin in physiological replacement or pharmacological doses. Design: We conducted two studies in healthy, eumenorrheic females, each comprising three separate admissions. In study 1, six women were maintained for 72 h 1) on isocaloric diet, 2) fasting while receiving placebo, or 3) fasting while receiving Metreleptin in physiological replacement doses. In study 2, five women were administered physiological or...

  • long term Metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women
    Metabolism-clinical and Experimental, 2011
    Co-Authors: Elizabeth Sienkiewicz, Sharon H Chou, John P Chamberland, Kalliopi M Arampatzi, Mary Brinkoetter, Konstantinos N. Aronis, Chuanyun Gao, Faidon Magkos, Anastasia Koniaris, Christos S Mantzoros
    Abstract:

    Strenuously exercising young women with hypothalamic amenorrhea are hypoleptinemic and have low bone mineral density (BMD) and content (BMC), which predispose them to increased fracture risk. Short-term leptin replacement in these women corrects many neuroendocrine abnormalities and increases circulating levels of bone formation markers. Whether treatment with recombinant methionyl human leptin (Metreleptin) for a long period improves BMD and BMC remains unknown. We studied 20 strenuously exercising young women with hypoleptinemia (leptin concentration <5 ng/mL) and hypothalamic amenorrhea of at least 6 months' duration. Eleven were randomized to Metreleptin (initial dose, 0.08 mg/[kg·d] for 3 months; altered thereafter to 0.12 mg/kg for lack of efficacy or 0.04 mg/[kg d] for more than 5% weight loss) and 9 were randomized to placebo for 9 months. After a 3-month washout period, subjects were reexamined at the 1-year time point. Six subjects elected to continue on open-label Metreleptin treatment for another 12 months. Two subjects dropped out after 18 months, and 4 completed the entire 2-year study. The BMD and BMC of the total body, lumbar spine (L1-L4), hip, and radius were assessed by using dual-energy x-ray absorptiometry at baseline and at 3, 6, 9, 12, 18, and 24 months of treatment. Metabolic and hormonal parameters and bone markers were measured in blood and urine. Metreleptin significantly increased BMC (P = .034) and tended to increase BMD (P = .069) at the lumbar spine at 9 months in the entire study group (intention-to-treat analysis). In subjects who completed the entire 2-year study (n = 4), Metreleptin significantly increased BMD (P = .024) and BMC (P = .049) at the lumbar spine by 4% to 6%. Changes were not significant at the whole body, hip, and radius. Changes in hormonal and metabolic parameters and bone markers were moderate during the first year of treatment, but Metreleptin further increased insulin-like growth factor 1 and decreased cortisol and cross-linked C-terminal telopeptide of type 1 collagen concentrations in serum during the second year of treatment (P < .05). The incremental area under the estradiol concentration curve over the 2-year course of the study correlated positively with the corresponding increase in lumbar spine BMD (ρ = 0.42, P = .039). Long-term Metreleptin administration in strenuously exercising young women with hypothalamic amenorrhea and hypoleptinemia increases lumbar spine BMD and BMC and alters bone remodeling milieu to favor bone accretion. Results from this pilot study should be confirmed by future, larger clinical trials and need to be extended by studying bone microarchitecture and fracture risk.

Rebecca J. Brown - One of the best experts on this subject based on the ideXlab platform.

  • effects of Metreleptin on patient outcomes and quality of life in generalized and partial lipodystrophy
    Journal of the Endocrine Society, 2021
    Co-Authors: Keziah Cook, Elaine Cochran, Kelly Adamski, Aparna Gomes, Edward Tuttle, Henner Kalden, Rebecca J. Brown
    Abstract:

    Generalized and partial lipodystrophy are rare and complex diseases with progressive clinical and humanistic burdens stemming from selective absence of subcutaneous adipose tissue, which causes reduced energy storage capacity and a deficiency of adipokines such as leptin. Treatment options were limited before leptin replacement therapy (Metreleptin) became available. This retrospective study evaluates both clinical and humanistic consequences of the disease and treatment. Chart data were abstracted from a cohort of Metreleptin-treated patients with generalized and partial lipodystrophy (n = 112) treated at the US National Institutes of Health. To quantify the quality-of-life consequences of the lipodystrophy disease attributes recorded in chart data, a discrete choice experiment was completed in 6 countries (US, n = 250; EU, n = 750). Resulting utility decrements were used to estimate the quality-adjusted life-year consequences of changes in lipodystrophy attribute prevalence before and after Metreleptin. In addition to metabolic impairment, patients with generalized and partial lipodystrophy experienced a range of lipodystrophy consequences, including liver abnormality (94%), hyperphagia (79%), impaired physical appearance (77%), kidney abnormality (63%), reproductive dysfunction (80% of females of reproductive age), and pancreatitis (39%). Improvement was observed in these attributes following initiation of Metreleptin. Quality-adjusted life-year gains associated with 12 months of treatment with Metreleptin were estimated at 0.313 for generalized and 0.117 for partial lipodystrophy, reducing the gap in quality of life between untreated lipodystrophy and perfect health by approximately 59% and 31%, respectively. This study demonstrates that Metreleptin is associated with meaningful clinical and quality-of-life improvements.

  • effects of Metreleptin on proteinuria in patients with lipodystrophy
    The Journal of Clinical Endocrinology and Metabolism, 2019
    Co-Authors: Ho Lim Lee, Elaine Cochran, Phillip Gorden, Meryl Waldman, Sungyoung Auh, James E Balow, Rebecca J. Brown
    Abstract:

    CONTEXT Patients with lipodystrophy have high prevalence of proteinuria. OBJECTIVE To assess kidney disease in patients with generalized (GLD) versus partial lipodystrophy (PLD), and effects Metreleptin on proteinuria in patients with lipodystrophy. DESIGN/SETTING/PATIENTS/INTERVENTION Prospective, open-label studies of Metreleptin treatment in patients with GLD and PLD at the National Institutes of Health, Bethesda, MD. OUTCOME MEASURES 24-hour urinary albumin and protein excretion rates, estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl) were measured at baseline and during up to 24 months of Metreleptin treatment. Patients with increases in medications affecting outcome measures were excluded. RESULTS At baseline, patients with GLD had significantly greater albuminuria, proteinuria, eGFR, and CrCl compared to patients with PLD. CrCl was above the normal range in 69% of patients with GLD, and 39% with PLD (P=0.02). With up to 24 months of Metreleptin treatment, there were significant reductions in albuminuria and proteinuria in patients with GLD, but not in those with PLD. No changes in eGFR or CrCl were observed in patients with GLD or PLD during Metreleptin treatment. CONCLUSIONS Patients with GLD had significantly greater proteinuria than those with PLD, which improved with Metreleptin treatment. The mechanisms leading to proteinuria in lipodystrophy and improvements in proteinuria with Metreleptin are not clear. Hyperfiltration was also more common in GLD versus PLD but did not change with Metreleptin.

  • advanced lipoprotein analysis shows atherogenic lipid profile that improves after Metreleptin in patients with lipodystrophy
    Journal of the Endocrine Society, 2019
    Co-Authors: Alexandra Kinzer, Robert D Shamburek, Marissa Lightbourne, Ranganath Muniyappa, Rebecca J. Brown
    Abstract:

    Context Patients with lipodystrophy have dyslipidemia and insulin resistance. Leptin treatment with Metreleptin in lipodystrophy decreases insulin resistance and lowers triglycerides without changing high-density lipoprotein. Detailed measurement of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel. We hypothesized that patients with lipodystrophy would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with Metreleptin treatment. Objective To characterize the lipoprotein profile in patients with lipodystrophy compared with controls and to evaluate effects of Metreleptin treatment. Design Setting Patients and Intervention Patients with lipodystrophy (N = 17) were studied before and after Metreleptin for 2 weeks and 6 months and compared with 51 insulin-sensitive sex-matched controls. Main Outcome Measures Lipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs). Results Patients with lipodystrophy had elevated large TRLPs and smaller HDLPs and LDLPs compared with controls. Five patients with lipodystrophy had chylomicrons, compared with zero controls. Metreleptin decreased the size and concentration of TRLPs, eliminated chylomicrons in all but one patient, decreased LDLPs, and increased LDLP size. Metreleptin treatment did not have major effects on HDLPs. Conclusions Patients with lipodystrophy had an atherogenic lipoprotein profile at baseline consistent with elevated CVD risk, which improved after Metreleptin treatment. The presence of fasting chylomicrons in a subset of patients with lipodystrophy suggests saturation of chylomicron clearance by lipoprotein lipase.

  • Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants.
    The Journal of Clinical Endocrinology & Metabolism, 2019
    Co-Authors: Hilal Sekizkardes, Elaine Cochran, Noemi Malandrino, Abhimanyu Garg, Rebecca J. Brown
    Abstract:

    Context Familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with Metreleptin has largely been studied in the LMNA group. Objective To understand the efficacy of Metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of Metreleptin responsiveness. Design Subgroup analysis of a prospective open-label study of Metreleptin in lipodystrophy. Setting National Institutes of Health, Bethesda, Maryland. Participants Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin Intervention Metreleptin (0.08 to 0.16 mg/kg) for 12 months. Outcome Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. Results Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of Metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P 8%. Conclusion Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of Metreleptin in patients with the two most common genetic causes of FPLD.

  • Metreleptin mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy
    Journal of Clinical Investigation, 2018
    Co-Authors: Rebecca J. Brown, Elaine Cochran, Areli Valencia, Megan Startzell, Peter Walter, Martin H Garraffo, Ahmed M Gharib, Ronald Ouwerkerk, Amber B Courville, Shanna Bernstein
    Abstract:

    BACKGROUND: Recombinant leptin (Metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether Metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS: Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with Metreleptin (n = 8) were continued on Metreleptin for 5 days and then taken off Metreleptin for the next 14 days (withdrawal cohort). This order was reversed in Metreleptin-naive patients (n = 14), who were reevaluated after 6 months of Metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS: With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping Metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with Metreleptin for 14 days (initiation cohort). In the initiation cohort only, Metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of Metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION: Using lipodystrophy as a human model of leptin deficiency and replacement, we show that Metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION: ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Konstantinos N. Aronis - One of the best experts on this subject based on the ideXlab platform.

  • gender dimorphism and lack of day night variation or effects of energy deprivation on undercarboxylated osteocalcin levels in humans
    Obesity, 2013
    Co-Authors: Joo-pin Foo, John P Chamberland, Konstantinos N. Aronis, Ole-petter R. Hamnvik, Bindiya Thakkar, Mary Brinkoetter
    Abstract:

    Objective Undercarboxylated osteocalcin (ucOC) is a bone marker with potent metabolic effects. Leptin regulates Esp gene expression and osteocalcin carboxylation in animal models. We aim to elucidate day/night patterns of ucOC levels, whether short-term and/or chronic energy deprivation alters ucOC levels, and whether leptin may mediate these changes in humans. Design and Methods Twelve healthy males and females were studied for 72 h in the fed state to study day/night pattern of ucOC. The six female subjects were also studied in a crossover interventional study in the fasting state for 72 h with administration of either placebo or Metreleptin in physiological doses. Blood samples were obtained hourly from 0800 a.m. on day 3 until 0800 a.m. on day 4. In a separate study, eleven obese subjects who underwent bariatric surgery were followed for 24 weeks to examine the effects of postsurgery weight loss on ucOC levels. Results Males have higher ucOC levels compared to females. There is no day/night variation pattern of circulating ucOC in humans. Short-term and chronic energy deprivation or leptin administrations do not alter ucOC levels. Conclusions The hypothesis that ucOC plays a role in energy homeostasis or of leptin in regulating ucOC in humans is not supported.

  • chemerin is expressed mainly in pancreas and liver is regulated by energy deprivation and lacks day night variation in humans
    European Journal of Endocrinology, 2013
    Co-Authors: John P Chamberland, Konstantinos N. Aronis, Reena Berman, Christos S Mantzoros
    Abstract:

    Objective: Chemerin is an adipocyte-secreted hormone and has recently been associated with obesity and the metabolic syndrome. Although studies in rodents have outlined the aspects of chemerin’s function and expression, its physiology and expression patterns are still to be elucidated in humans. Methods: To evaluate for any day/night variation in chemerin secretion, we analyzed hourly serum samples from six females in the fed state. To examine whether energy deprivation affects chemerin levels, and whether this could be mediated through leptin, we analyzed samples from the same subjects in the fasting state while administering either placebo or leptin. To evaluate for any potential dose– effect relationship between leptin and chemerin, we administered increasing Metreleptin doses to five females. A tissue array was used to study the expression of chemerin in different human tissues. Ex vivo treatment of human fat explants from three subjects with leptin was carried out to evaluate for any direct effect of leptin on adipocyte chemerin secretion. Results: Chemerin does not display a day/night variation, while acute energy deprivation resulted in a significant drop in circulating chemerin levels by w42%. The latter was unaltered by Metreleptin administration, and leptin administration did not affect the secretion of chemerin by human adipose tissue studied ex vivo. Chemerin was expressed primarily in the pancreas and liver. Chemerin receptor showed increased expression in the lymph nodes and the spleen. Conclusions: We outline for the first time chemerin expression and physiology in humans, which are different from those in mice.

  • fibroblast growth factor 21 levels in young healthy females display day and night variations and are increased in response to short term energy deprivation through a leptin independent pathway
    Diabetes Care, 2013
    Co-Authors: Joo-pin Foo, John P Chamberland, Christos S Mantzoros, Konstantinos N. Aronis, Jason Paruthi, Hyun Seuk Moon
    Abstract:

    OBJECTIVE Fibroblast growth factor (FGF)-21 is an endocrine factor with potent metabolic effects. Its day–night patterns of secretion and/or its physiological response to energy deprivation and relationship to free fatty acids (FFAs) and/or leptin remain to be fully elucidated. We aim to elucidate day–night pattern of FGF-21 levels and its relationship to FFA, to assess whether energy deprivation alters its circulating patterns, and to examine whether leptin may mediate these changes. RESEARCH DESIGN AND METHODS Six healthy lean females were studied for 72 h in a cross-over interventional study under three different conditions: on isocaloric diet and in a fasting state with administration of either placebo or Metreleptin in physiological replacement doses. Blood samples were obtained hourly from 8:00 a.m. on day 4 until 8:00 a.m. on day 5. RESULTS FGF-21 exhibited day–night variation pattern during the isocaloric fed state. Fasting significantly increased FGF-21 levels ( P CONCLUSIONS A day–night variation in the levels of FGF-21 exists in young lean females in the fed state. Energy deprivation increases FGF-21 levels via a leptin-independent pathway. The interaction between FGF-21 and starvation-induced lipolysis, as indicated by its close cross-correlations with FFA in both fed state and energy deprivation, needs to be studied further.

  • short term energy deprivation alters activin a and follistatin but not inhibin b levels of lean healthy women in a leptin independent manner
    The Journal of Clinical Endocrinology and Metabolism, 2011
    Co-Authors: Vasiliki A Moragianni, John P Chamberland, Christos S Mantzoros, Konstantinos N. Aronis
    Abstract:

    Context: Leptin is a potent modulator of the hypothalamic-pituitary-gonadal axis mediating the effect of energy deprivation on several hypothalamic-pituitary-peripheral axes. Activin A, inhibin B, and follistatin (FST) also regulate the hypothalamic-pituitary-gonadal axis in humans. It remains unknown whether energy deprivation affects these hormone levels in a leptin-dependent or -independent manner. Objective: We investigated 1) day-night variability patterns of activin, inhibin, and FST in the fed state, 2) whether their levels are affected by fasting, and 3) whether such an effect is mediated by leptin in physiological replacement or pharmacological doses. Design: We conducted two studies in healthy, eumenorrheic females, each comprising three separate admissions. In study 1, six women were maintained for 72 h 1) on isocaloric diet, 2) fasting while receiving placebo, or 3) fasting while receiving Metreleptin in physiological replacement doses. In study 2, five women were administered physiological or...

  • long term Metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women
    Metabolism-clinical and Experimental, 2011
    Co-Authors: Elizabeth Sienkiewicz, Sharon H Chou, John P Chamberland, Kalliopi M Arampatzi, Mary Brinkoetter, Konstantinos N. Aronis, Chuanyun Gao, Faidon Magkos, Anastasia Koniaris, Christos S Mantzoros
    Abstract:

    Strenuously exercising young women with hypothalamic amenorrhea are hypoleptinemic and have low bone mineral density (BMD) and content (BMC), which predispose them to increased fracture risk. Short-term leptin replacement in these women corrects many neuroendocrine abnormalities and increases circulating levels of bone formation markers. Whether treatment with recombinant methionyl human leptin (Metreleptin) for a long period improves BMD and BMC remains unknown. We studied 20 strenuously exercising young women with hypoleptinemia (leptin concentration <5 ng/mL) and hypothalamic amenorrhea of at least 6 months' duration. Eleven were randomized to Metreleptin (initial dose, 0.08 mg/[kg·d] for 3 months; altered thereafter to 0.12 mg/kg for lack of efficacy or 0.04 mg/[kg d] for more than 5% weight loss) and 9 were randomized to placebo for 9 months. After a 3-month washout period, subjects were reexamined at the 1-year time point. Six subjects elected to continue on open-label Metreleptin treatment for another 12 months. Two subjects dropped out after 18 months, and 4 completed the entire 2-year study. The BMD and BMC of the total body, lumbar spine (L1-L4), hip, and radius were assessed by using dual-energy x-ray absorptiometry at baseline and at 3, 6, 9, 12, 18, and 24 months of treatment. Metabolic and hormonal parameters and bone markers were measured in blood and urine. Metreleptin significantly increased BMC (P = .034) and tended to increase BMD (P = .069) at the lumbar spine at 9 months in the entire study group (intention-to-treat analysis). In subjects who completed the entire 2-year study (n = 4), Metreleptin significantly increased BMD (P = .024) and BMC (P = .049) at the lumbar spine by 4% to 6%. Changes were not significant at the whole body, hip, and radius. Changes in hormonal and metabolic parameters and bone markers were moderate during the first year of treatment, but Metreleptin further increased insulin-like growth factor 1 and decreased cortisol and cross-linked C-terminal telopeptide of type 1 collagen concentrations in serum during the second year of treatment (P < .05). The incremental area under the estradiol concentration curve over the 2-year course of the study correlated positively with the corresponding increase in lumbar spine BMD (ρ = 0.42, P = .039). Long-term Metreleptin administration in strenuously exercising young women with hypothalamic amenorrhea and hypoleptinemia increases lumbar spine BMD and BMC and alters bone remodeling milieu to favor bone accretion. Results from this pilot study should be confirmed by future, larger clinical trials and need to be extended by studying bone microarchitecture and fracture risk.

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  • effects of Metreleptin on proteinuria in patients with lipodystrophy
    The Journal of Clinical Endocrinology and Metabolism, 2019
    Co-Authors: Ho Lim Lee, Elaine Cochran, Phillip Gorden, Meryl Waldman, Sungyoung Auh, James E Balow, Rebecca J. Brown
    Abstract:

    CONTEXT Patients with lipodystrophy have high prevalence of proteinuria. OBJECTIVE To assess kidney disease in patients with generalized (GLD) versus partial lipodystrophy (PLD), and effects Metreleptin on proteinuria in patients with lipodystrophy. DESIGN/SETTING/PATIENTS/INTERVENTION Prospective, open-label studies of Metreleptin treatment in patients with GLD and PLD at the National Institutes of Health, Bethesda, MD. OUTCOME MEASURES 24-hour urinary albumin and protein excretion rates, estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl) were measured at baseline and during up to 24 months of Metreleptin treatment. Patients with increases in medications affecting outcome measures were excluded. RESULTS At baseline, patients with GLD had significantly greater albuminuria, proteinuria, eGFR, and CrCl compared to patients with PLD. CrCl was above the normal range in 69% of patients with GLD, and 39% with PLD (P=0.02). With up to 24 months of Metreleptin treatment, there were significant reductions in albuminuria and proteinuria in patients with GLD, but not in those with PLD. No changes in eGFR or CrCl were observed in patients with GLD or PLD during Metreleptin treatment. CONCLUSIONS Patients with GLD had significantly greater proteinuria than those with PLD, which improved with Metreleptin treatment. The mechanisms leading to proteinuria in lipodystrophy and improvements in proteinuria with Metreleptin are not clear. Hyperfiltration was also more common in GLD versus PLD but did not change with Metreleptin.

  • long term effectiveness and safety of Metreleptin in the treatment of patients with partial lipodystrophy
    Endocrine, 2018
    Co-Authors: Elif A Oral, Elaine Cochran, Phillip Gorden, David Araujovilar, David B Savage, Alison Long, Gregory M Fine, Taylor Salinardi, Rebecca J. Brown
    Abstract:

    The purpose of this study is to summarize the effectiveness and safety of Metreleptin in patients with congenital or acquired generalized lipodystrophy. Patients (n = 66) aged ≥6 months had lipodystrophy, low circulating leptin, and ≥1 metabolic abnormality (diabetes mellitus, insulin resistance, or hypertriglyceridemia). Metreleptin dose (once or twice daily) was titrated to a mean dose of 0.10 mg/kg/day with a maximum of 0.24 mg/kg/day. Means and changes from baseline to month 12 were assessed for glycated hemoglobin (HbA1c), fasting triglycerides (TGs), and fasting plasma glucose (FPG). Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at months 4, 12, and 36, medication changes, and estimates of liver size. Treatment-emergent adverse events (TEAEs) were recorded. Significant mean reductions from baseline were seen at month 12 for HbA1c (–2.2%, n = 59) and FPG (–3.0 mmol/L, n = 59) and mean percent change in fasting TGs (–32.1%, n = 57) (all p ≤ 0.001). Reductions from baseline over time in these parameters were also significant at month 36 (all p < 0.001, n = 14). At month 4, 34.8% of patients had a ≥1% reduction in HbA1c and 62.5% had a ≥30% reduction in fasting TGs; at month 12, 80% of patients had a ≥1% decrease in HbA1c or ≥30% decrease in TGs, and 66% had a decrease of ≥2% in HbA1c or ≥40% decrease in TGs. Of those on medications, 41%, 22%, and 24% discontinued insulin, oral antidiabetic medications, or lipid-lowering medications, respectively. Mean decrease in liver volume at month 12 was 33.8% (p < 0.001, n = 12). Most TEAEs were of mild/moderate severity. In patients with generalized lipodystrophy, long-term treatment with Metreleptin was well tolerated and resulted in sustained improvements in hypertriglyceridemia, glycemic control, and liver volume.

  • effects of Metreleptin in pediatric patients with lipodystrophy
    The Journal of Clinical Endocrinology and Metabolism, 2017
    Co-Authors: Rebecca J. Brown, Elaine Cochran, Cristina Adelia Meehan, Kristina I Rother, Mary Walter, David E Kleiner, Phillip Gorden
    Abstract:

    Context Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin. Objective Determine effects of Metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin. Design Prospective, single-arm, open-label studies with continuous enrollment since 2000. Setting National Institutes of Health, Bethesda, Maryland. Patients Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia). Intervention Subcutaneous Metreleptin injections (0.04 to 0.19 mg/kg/d). Main Outcome Measures Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment. Results After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of Metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty. Conclusion Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

  • Metreleptin therapy lowers plasma angiopoietin like protein 3 in patients with generalized lipodystrophy
    Journal of Clinical Lipidology, 2017
    Co-Authors: Ranganath Muniyappa, Elaine Cochran, Phillip Gorden, Brent S Abel, Mary Walter, Alan T Remaley, Asha Asthana, Monica C Skarulis, Rebecca J. Brown
    Abstract:

    Background Reduced triglyceride clearance due to impaired lipoprotein lipase–mediated lipolysis contributes to severe hypertriglyceridemia in lipodystrophy. Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) impair clearance of triglycerides by inhibiting lipoprotein lipase. Whether circulating ANGPTL3/4 levels are altered in lipodystrophy and the effects of leptin replacement on these ANGPTLs are unknown. Objective To examine if ANGPTL3/4 levels are elevated in patients with generalized lipodystrophy and assess the effects of leptin replacement on these ANGPTLs. Methods Preleptin treatment plasma levels of ANGPTLs in patients with generalized lipodystrophy (n = 22) were compared with healthy controls (n = 39) using a post hoc case-control study design. In a prospective open-label study, we studied the effects of Metreleptin therapy (16–32 weeks) on plasma ANGPTL3/4 in patients with generalized lipodystrophy. Results Plasma ANGPTL3 (geometric mean [95% confidence interval]; 223 [182–275] vs 174 ng/mL [160–189], P  = .02) but not ANGPTL4 levels (55 [37–81] vs 44 ng/mL [37–52], P  = .26) were higher in patients with lipodystrophy compared with healthy controls. There was a significant decrease in total cholesterol, triglycerides, and glycosylated hemoglobin (A1C) levels following Metreleptin therapy. After Metreleptin, ANGPTL3 concentrations decreased significantly (223 [182–275] vs 175 ng/mL [144–214], P  = .01) with no change in ANGPTL4 (55 [37–81] vs 48 ng/mL [32–73], P  = .11). Conclusions These findings suggest that elevated plasma levels of ANGPTL3 in leptin-deficient states is attenuated with leptin therapy.

  • Immunogenicity associated with Metreleptin treatment in patients with obesity or lipodystrophy.
    Clinical endocrinology, 2016
    Co-Authors: Jean L. Chan, Elaine Cochran, Phillip Gorden, Elif A Oral, Joy Koda, Joseph S. Heilig, Rebecca J. Brown
    Abstract:

    SummaryObjective Recombinant human leptin (Metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antiMetreleptin antibody development, including in vitro neutralizing activity. Design Two randomized controlled studies in patients with obesity (twice-daily Metreleptin ± pramlintide for 20–52 weeks; 2006–2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily Metreleptin for 2 months to 12·3 years; 2000–2014). Patients A total of 579 Metreleptin-treated patients with obesity and 134 Metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105). Measurements AntiMetreleptin antibodies, in vitro neutralizing activity. Results AntiMetreleptin antibodies developed in most patients (obese: 96–100%; lipodystrophy: 86–92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4–6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on Metreleptin. Conclusions Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.