Effects Of Leptin Replacement Therapy Research Articles

When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin.

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

Metabolomic Analysis of the Effects of Leptin Replacement Therapy in Patients with Lipodystrophy.

Leptin treatment has dramatic clinical effects on glucose and lipid metabolism in leptin-deficient patients with lipodystrophy. Further elucidation of metabolic effects of exogenous leptin therapy will shed light on understanding leptin physiology in humans. Our objective was to utilize metabolomic profiling to examine the changes associated with administration of short-term metreleptin therapy in patients with lipodystrophy. We conducted a pre-post-treatment study in 19 patients (75% female) with varying forms of lipodystrophy (congenital generalized lipodystrophy, n = 10; acquired generalized lipodystrophy, n = 1; familial partial lipodystrophy, n = 8) who received daily subcutaneous metreleptin injections for a period of 16 to 23 weeks. A 3-hour oral glucose tolerance test and body composition measurements were conducted before and after the treatment period, and fasting blood samples were used for metabolomic profiling. The study outcome aimed at measuring changes in physiologically relevant metabolites before and after leptin therapy. Metabolomic analysis revealed changes in pathways involving branched-chain amino acid metabolism, fatty acid oxidation, protein degradation, urea cycle, tryptophan metabolism, nucleotide catabolism, vitamin E, and steroid metabolism. Fold changes in pre- to post-treatment metabolite levels indicated increased breakdown of fatty acids, branched chain amino acids proteins, and nucleic acids. Leptin replacement therapy has significant effects on important metabolic pathways implicated in patients with lipodystrophy. Continued metabolomic studies may provide further insight into the mechanisms of action of leptin replacement therapy and provide novel biomarkers of lipodystrophy.Abbreviations: 1,5-AG, 1,5-anhydroglucitol; 11βHSD1, 11-β hydroxysteroid dehydrogenase 1; BCAA, branched-chain amino acid; FFA, free fatty acid; GC-MS, gas chromatography mass spectrometry; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-γ; m/z, mass to charge ratio; OGTT, oral glucose tolerance test; TDO, tryptophan 2,3-dioxygenase; TNF-α, tumor necrosis factor-α; UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometry.

Leptin Replacement Therapy Improves Endothelial Function and Vascular Inflammation in a Mouse Model of Acquired Lipodystrophy Associated with Antiretroviral Treatment by Regulating Nox1‐Derived ROS and C‐C Chemokine Receptor Type 5

Highly active antiretroviral therapy (HAART) has been used at suppressing HIV replication, as a side effect HAART promotes lipodystrophy, which is a metabolic disorder characterized by an abnormal adipose tissue distribution, reduced leptin plasma levels and vascular complications. Leptin replacement therapy (LRT) is currently used to treat metabolic dysfunctions in patients diagnosed with congenital lipodystrophy. Here, we sought to investigate whether LRT restores vascular function and reduces inflammation in mice treated with the antiretroviral agent, ritonavir. Four weeks of ritonavir reduced body weight [control (C): 28.4±0.5 vs. Rit: 24.4 ± 0.2g*, *P<0.05], fat mass (C: 10 ± 0.4 vs. Rit: 4.5 ± 0.9 %*, *P<0.05) and leptin plasma levels (C: 4.7 ± 0.05 vs. Rit: 2.0 ± 0.36 ng/mL*, *P<0.05) confirming that it induces acquired lipodystrophy. Acquired lipodystrophy impaired endothelial function, increased plasma lipid peroxidation and vascular H2O2, and ROS producing enzymes (Nox1 and NoxA1). Furthermore, acquired lipodystrophy was associated with vascular inflammation characterized by elevation of NLRP3, Caspase‐1, IL‐1β, MCP‐1, F4/80, CCR5 and CCL5 gene expression. ROS scavenging via tempol (SOD mimetic, 100 μmol/l) or GKT771 (Nox1 inhibitor, 10 μmol/l) restored endothelial function. LRT (10μg/day/7 days, osmotic mini‐pump), at the end of the 3‐week ritonavir, restored endothelial function, reduced vascular oxidative stress and Nox1 and NOXA1 gene expression and vascular inflammation. Nox1 deficiency (Nox1−/−) protected mice from acquired lipodystrophy‐induced endothelial dysfunction and reduced inflammatory markers including CCR5 and CCL5. In order to analyze whether vascular inflammation is occurring via CCR5/CCL5, we induced lipodystrophy in CCR5 deficient mice (CCR5−/−). These mice were protected from acquired lipodystrophy‐induced endothelial dysfunction and vascular inflammation. Moreover, deleting endothelial leptin signaling via specific deletion of leptin receptor (LepR) in endothelial cells (LepR−/−EC mice) promoted endothelial dysfunction, which was reverted by pre‐incubating aortic rings with Nox1 inhibitor (GKT771) in vitro and increased inflammatory markers. Furthermore, LepR−/−EC mice were resistant to the vascular protective effects of LRT. Taken all together, LRT restores endothelial function and reduces vascular inflammation in acquired lipodystrophy associated with HAART via endothelium dependent reduction in Nox1‐derived ROS and CCR5/CCL5. Taken together these data support a key role for endothelial leptin signaling in the control of vascular tone and inflammation and suggest that LRT could represent a potential new avenue for the treatment of vascular diseases associated with acquired lipodystrophy.Support or Funding InformationWork supported by 17POST33410363 and 1K99HL140139‐01A1 to TBN and 1R01HL13030101 to EJ.BdC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Patient Quality of Life and Benefits of Leptin Replacement Therapy (LRT) in Generalized and Partial Lipodystrophy (GL, PL)

Effects of LRT on metabolic disease in GL and PL have been studied; however, little is known about consequences of GL and PL, or the effect of LRT, on quality of life (QoL). To characterize health utility consequences of GL and PL attributes on patients, a discrete choice experiment (following a tutorial on the disease) was conducted with 1,000 members of the general population. Multinomial logit regression was used to estimate utility decrements associated with each attribute using an approach similar to Bansback et al. (2012). Results were combined with data on prevalence of attributes before and after 1 year of LRT, derived from a retrospective chart review, to assess overall QoL consequences of GL, PL, and the impact of LRT in Quality-Adjusted Life Years (QALYs). Overall, QALY gains associated with LRT were estimated at 0.423 across all patients. Impaired work/school ability, hyperphagia and organ damage were the largest contributing attributes. A subgroup analysis for GL and PL found total QALY gains associated with LRT were 0.569 and 0.199, respectively. This study indicates that lipodystrophy is associated with a large QoL impairment and that the benefits of LRT may be substantial in these patients. Attribute utility decrements appear to be consistent with those reported in other research (e.g., for diabetes), yet the cumulative impact of attributes makes the burden of GL and PL high. Disclosure O.A. Ali: Consultant; Self; Aegerion Pharmaceuticals. K. Cook: Consultant; Self; Aegerion Pharmaceuticals. K.S. Shampanier: Consultant; Self; Aegerion Pharmaceuticals. E. Tuttle: Consultant; Self; Aegerion Pharmaceuticals. C. Gerrits: None. R. Brown: None.

Effect of Leptin Replacement Therapy (LRT) on Survival and Disease Progression in Generalized and Partial Lipodystrophy (GL, PL)

Lipodystrophy (LD) is an ultra-rare disease associated with significant morbidity and mortality. Effects of LRT on metabolic disease in GL and PL have been studied; but effects on mortality are unknown. We investigated these effects using data from GL and PL patients treated with LRT at NIH (N=114) and cared for but not treated with LRT at 3 centers in the U.S. and Turkey (N=178). Four abnormalities (liver, kidney, heart, and HbA1c ≥6.5%) were considered. LRT patients had a mean of 2.8 abnormalities prior to treatment, while the mean for untreated patients was 0.7 at a similar age. We used a matching approach to create comparable samples of treated and untreated patients. Each treated patient was matched (using Mahalanobis distance) to an untreated patient to balance across age, gender, type of LD, and number of abnormalities. LRT treatment effect was examined via Cox proportional hazards models of 1) mortality and 2) development of subsequent abnormalities. Additionally, the relationship between abnormalities and mortality was studied in the sample of untreated patients. Results: A Cox proportional hazards model relating treatment to mortality yielded a hazard ratio (HR) for LRT of 0.34 (p=0.047), meaning that LRT was associated with a 66% decrease in mortality risk. Adjusting for covariates including gender, type of LD, and type of abnormality resulted in a larger decrease in mortality risk (HR 0.21, p<.01). One possible mechanism for the effect of LRT on mortality is its role in mitigating or resolving abnormalities. A time-varying Cox proportional hazards model relating number of abnormalities present (0 to 4) to mortality among untreated patients found a positive relationship between additional abnormalities and mortality (HR 3.2, p<.01). Separately, we found that LRT reduced the likelihood of developing a third (HR 0.47, p<.01) or fourth abnormality (HR 0.46, p<.05). In conclusion, these are the first data suggesting that LRT reduces mortality in LD. Disclosure O.A. Ali: Consultant; Self; Aegerion Pharmaceuticals. K. Cook: Consultant; Self; Aegerion Pharmaceuticals. D. Gupta: Consultant; Self; Aegerion Pharmaceuticals. D. Holmqvist: Consultant; Self; Aegerion Pharmaceuticals. D. Lee: Consultant; Self; Aegerion Pharmaceuticals. C.K. Ng: Consultant; Self; Aegerion Pharmaceuticals. P. Bradt: Employee; Self; Aegerion Pharmaceuticals. R. Brown: None.

Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis.

The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D.

Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis.

In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic gluconeogenesis and fasting hyperglycaemia in rodent models of poorly controlled diabetes. On the basis of these studies we conclude with a view of the potential therapeutic applications of leptin replacement therapy in humans. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Christoffer Clemmensen and colleagues, DOI: 10.1007/s00125-016-3906-7 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).

Effects of Leptin Replacement Therapy on Pancreatic β-Cell Function in Patients With Lipodystrophy

OBJECTIVELeptin administration is known to directly modulate pancreatic β-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on β-cell function are lacking. In this study, we examined the effects (16–20 weeks) of leptin replacement on β-cell function in patients with lipodystrophy.RESEARCH DESIGN AND METHODSIn a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on β-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16–20 weeks of leptin replacement. β-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT.RESULTSThere was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, β-cell glucose sensitivity, rate sensitivity, or insulin clearance.CONCLUSIONSIn contrast to the suppressive effects of leptin on β-cell function in rodents, 16–20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or β-cell function in leptin-deficient individuals with lipodystrophy.

The role of leptin in obesity and the potential for leptin replacement therapy

Leptin (from the Greek word "lepto'' meaning "thin") is a 167-amino acid peptide hormone encoded by the obesity (ob) gene and secreted by white adipocytes. Blood leptin concentrations are increased in obese individuals. Leptin is a satiety hormone that provides negative feedback to the hypothalamus, controlling appetite and energy expenditure. Leptin binds to presynaptic GABAergic neurons to produce its effect, raising the distinct possibility that GABAergic axon terminals are the ultimate subcellular site of action for its effects. Released into the circulation, leptin crosses the blood-brain barrier and binds to leptin receptors, influencing the activity of various hypothalamic neurons, as well as encoding orexigenic and anorexigenic neuropeptides. Moreover, leptin affects a wide range of metabolic functions in the peripheral tissue. In this review, we discuss some physiologic functions of leptin, including effects on obesity and some effects of leptin replacement therapy.

Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy

To describe our 10-year experience in treating leptin-deficient humans. Three adults and one boy presented with childhood-onset morbid obesity, hypogonadism and family history of obesity and early death. Serum leptin was inappropriately low. A recessive C105T leptin gene mutation was identified. Metabolic and endocrine assessments were conducted, before and while on and off leptin. The adults' body mass index decreased from 51.2 ± 2.5 to 29.5 ± 2.8 kg/m(2). Serum lipids normalized, insulin resistance decreased, and one of the initially diabetic females became normoglycemic. Hypogonadotropic hypogonadism was reversed, and other changes were observed in the adrenal, sympathetic, somatotropic and thyroid functions. Leptin replacement therapy reverses endocrine and metabolic alterations associated with leptin deficiency. Some of these results may be extrapolated to other diseases.