Person:

Mantzoros, Christos

Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis. In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes. Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of the aforementioned axes aimed at promoting survival. More specifically, gonadotropin levels decrease and become less pulsatile under conditions of energy deprivation, and these changes can be at least partially reversed through leptin administration in physiological replacement doses. Similarly, leptin deficiency is associated with thyroid axis abnormalities including abnormal levels of thyrotropin-releasing hormone, and leptin administration may at least partially attenuate this effect. Leptin deficiency results in decreased insulin-like growth factor 1 levels which can be partially ameliorated through leptin administration, and leptin appears to have a much more pronounced effect on the growth of rodents than that of humans. Similarly, adrenal axis function is regulated more tightly by low leptin in rodents than in humans. In addition to congenital leptin deficiency, conditions that may be associated with decreased leptin levels include hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes. Accumulating evidence from proof of concept studies suggests that leptin administration, in replacement doses, may ameliorate neuroendocrine abnormalities in individuals who suffer from these conditions.

Background: Findings from observational studies suggest that sex hormone-binding globulin (SHBG) and endogenous sex hormones may be mediators of the putative relation between coffee consumption and lower risk of type 2 diabetes. The objective of this study was to evaluate the effects of caffeinated and decaffeinated coffee on SHBG and sex hormone levels. Findings: After a two-week run-in phase with caffeine abstention, we conducted an 8-week parallel-arm randomized controlled trial. Healthy adults (n = 42) were recruited from the Boston community who were regular coffee consumers, nonsmokers, and overweight. Participants were randomized to five 6-ounce cups of caffeinated or decaffeinated instant coffee or water (control group) per day consumed with each meal, mid-morning, and mid-afternoon. The main outcome measures were SHBG and sex hormones [i.e., testosterone, estradiol, dehydroepiandrosterone sulfate]. No significant differences were found between treatment groups for any of the studied outcomes at week 8. At 4 weeks, decaffeinated coffee was associated with a borderline significant increase in SHBG in women, but not in men. At week 4, we also observed several differences in hormone concentrations between the treatment groups. Among men, consumption of caffeinated coffee increased total testosterone and decreased total and free estradiol. Among women, decaffeinated coffee decreased total and free testosterone and caffeinated coffee decreased total testosterone. Conclusions: Our data do not indicate a consistent effect of caffeinated coffee consumption on SHBG in men or women, however results should be interpreted with caution given the small sample size. This is the first randomized trial investigating the effects of caffeinated and decaffeinated coffee on SHBG and sex hormones and our findings necessitate further examination in a larger intervention trial.

OBJECTIVE To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults. RESEARCH DESIGN AND METHODS Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals. RESULTS Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39–0.63]) and HMW adiponectin (0.42 [0.32–0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables. CONCLUSIONS In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.

Objective: Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes. Research Design and Methods: We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro. Results: In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA({1c}) marginally (8.01 (\pm) 0.93–7.96 (\pm) 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of (\sim)50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at (\sim)50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling. Conclusions: In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA({1c}) marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes.

Leptin, an adipocyte-secreted hormone, regulates energy homeostasis as well as reproductive, neuroendocrine, immune and metabolic functions. Subjects with decreased amounts of fat in their adipose tissue, i.e., lipoatrophy, have low leptin levels. In the context of open-label, uncontrolled studies leptin administration, in physiological replacement doses, has been shown to have metabolically salutary effects in the rare patients with the syndrome of congenital lipodystrophy accompanied by leptin deficiency. Much more patients with lipodystrophy suffer from lipodystrophy and the metabolic syndrome associated with the use of highly active antiretroviral therapy. In this so called highly active antiretroviral therapy (HAART)-associated lipodystrophy and metabolic syndrome, patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Leptin administration has been shown to decrease central fat mass and to improve fasting insulin/glucose levels and insulin sensitivity in human immunodeficiency virus-infected hypoleptinemic patients with HAART induced lipodystrophy and the metabolic syndrome. By contrast, the results of leptin treatment in leptin replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. In this review, we present the emerging clinical applications and potential therapeutic uses of leptin in humans with lipodystrophy and the metabolic syndrome.

Objective: Lactation has been associated with reduced maternal risk of type 2 diabetes, the metabolic syndrome, and cardiovascular disease. We examined the relationship between breastfeeding duration and maternal adipokines at 3 years postpartum. Research Design and Methods: We used linear regression to relate the duration of lactation to maternal leptin, adiponectin, ghrelin, and peptide YY (PYY) at 3 years postpartum among 570 participants with 3-year postpartum blood samples (178 fasting), prospectively collected lactation history, and no intervening pregnancy in Project Viva, a cohort study of mothers and children. Results: A total of 88% of mothers had initiated breastfeeding, 26% had breastfed (\geq 12) months, and 42% had exclusively breastfed for (\geq 3) months. In multivariate analyses, we found that duration of total breastfeeding was directly related to PYY and ghrelin, and exclusive breastfeeding duration was directly related to ghrelin (predicted mean for never exclusively breastfeeding: 790.6 pg/mL vs. (\geq 6) months of exclusive breastfeeding: 1,008.1 pg/mL; P < 0.01) at 3 years postpartum, adjusting for pregravid BMI, gestational weight gain, family history of diabetes, parity, smoking status, and age. We found a nonlinear pattern of association between exclusive breastfeeding duration and adiponectin in multivariate-adjusted models. Conclusions: In this prospective cohort study, we found a direct relationship between the duration of lactation and both ghrelin and PYY at 3 years postpartum.

Context and Objective The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). Design and Participants A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. Results: Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. Conclusions: Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. Trial Registration ClinicalTrials.gov NCT00317993 NCT00317993.

Objective: To study the day-night variation of omentin-1 levels and assess whether leptin, and/or short-and long-term energy deprivation alter circulating omentin-1 levels via cytokines. Design and Methods Omentin-1 levels were measured hourly in serum samples from six healthy men to evaluate for day-night variation. To study effects of acute energy deprivation and of leptin administration, eight healthy subjects were studied in the fasting state for 72 hours with administration of either placebo or metreleptin in physiological replacement doses. We evaluated the effect of leptin in pharmacological doses on serum omentin-1 and cytokine levels, as well as on omentin-1 levels in ex vivo omental adipose tissue, in fifteen healthy volunteers. To study the effect of chronic energy deprivation and weight loss on omentin-1 levels we followed eighteen obese subjects for 12 months who underwent bariatric surgery. Results: There is no day-night variation in omentin-1 levels. Short-term and chronic energy deprivation as well as ex vivo leptin administration and physiological replacement doses of leptin do not alter omentin-1 levels, whereas pharmacologic doses of metreleptin reduce omentin-1 levels whereas levels of TNF-α receptor II and IL-6 tend to increase. Conclusions: Omentin-1 levels are reduced by pharmacological doses of metreleptin independent of effects on cytokine levels.

Objective: We examined associations of perinatal and 3-year leptin with weight gain and adiposity through 7 years. Design and Methods In Project Viva, we assessed plasma leptin from mothers at 26–28 weeks’ gestation (n=893), umbilical cord vein at delivery (n=540), and children at 3 years (n=510) in relation to body mass index (BMI) z-score, waist circumference, skinfold thicknesses, and dual X-ray absorptiometry body fat. Results: 50.1% of children were male and 29.5% non-white. Mean(SD) maternal, cord, and age 3 leptin concentrations were 22.9(14.2), 8.8(6.4), and 1.8(1.7) ng/mL, respectively, and 3- and 7-year BMI z-scores were 0.46(1.00) and 0.35(0.97), respectively. After adjusting for parental and child characteristics, higher maternal and cord leptin was associated with less 3- year adiposity. For example, mean 3-year BMI z-score was 0.5 lower (95%CI:−0.7,−0.2; p-trend=0.003) among children whose mothers’ leptin concentrations were in the top vs. bottom quintile. In contrast, higher age 3 leptin was associated with greater weight gain and adiposity through age 7 [e.g., change in BMI z-score from 3 to 7 years was 0.2 units (95%CI:−0.0,0.4; p-trend=0.05)]. Conclusions: Higher perinatal leptin was associated with lower 3-year adiposity, whereas higher age 3 leptin was associated with greater weight gain and adiposity by 7 years.

Irisin, secreted by skeletal muscle and possibly fat, is hypothesized to play an important role in modulating energy expenditure, obesity and metabolism. Coffee consumption also increases energy expenditure and leads to positive metabolic effects, but whether these effects are mediated by irisin remains unknown. The objective of this study was to determine the association between baseline irisin levels and the metabolic profile in humans and to investigate whether consumption of caffeinated coffee alters irisin levels. To this end, a secondary analysis was performed investigating irisin levels at baseline and after eight weeks in 32 healthy, overweight coffee drinkers who were randomized to consumption of 5 cups per day of instant caffeinated coffee, decaffeinated coffee, or water. Spearman correlation and analysis of covariance analyses were performed to identify possible associations. Irisin levels were positively correlated with waist circumference (r = 0.41, p = 0.02), fat mass (r = 0.44, p = 0.01) and CRP (r = 0.47, p = 0.007). Though there was a trend towards increased levels of irisin over time in the caffeinated coffee group (+1.8%) when compared to the placebo group (−4%) this did not reach statistical significance (p = 0.75 for the trend). This first randomized trial failed to reveal any effects of coffee consumption on irisin levels, but a larger trial, appropriately sized on the basis of data provided by this study, is needed to conclusively investigate such a relationship. Trial Registration Clinicaltrials.gov NCT00305097