Leptin in Relation to the Lipodystrophy-Associated Metabolic Syndrome

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

Leptin and Its Emerging Role in Children and Adolescents

Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent “proof of concept” studies involving leptin administration to humans support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/ caloric deprivation. Moreover, interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. The potential clinical usefulness of leptin in several disease states in children and adolescents, including hypothalamic amenorrhea, eating disorders and syndromes of insulin resistance is still under investigation

The Development of INT131 as a Selective PPARγ Modulator: Approach to a Safer Insulin Sensitizer

INT131 (formerly T0903131, T131, AMG131) is a potent non-thiazolidinedione (TZD) selective peroxisome proliferator-activated receptor γ modulator (SPPARM) currently in Phase 2 clinical trials for treatment of type-2 diabetes mellitus (T2DM). This new chemical entity represents a second generation SPPARM approach developed after the first generation PPARγ full agonists to address their inherent limitations. INT131 was specifically and carefully designed using preclinical models to exhibit a biological profile of strong efficacy with de minimis side effects compared to PPARγ full agonists. As a potent PPARγ modulator, INT131 binds to PPARγ with high affinity. In pharmacology models of diabetes and in early clinical studies, it achieved a high level of efficacy in terms of antidiabetic actions such as insulin sensitization and glucose and insulin lowering, but had little activity in terms of other, undesired, effects associated with TZD PPARγ full agonists such as edema and adipogenesis. Ongoing clinical development is directed at translating these findings into establishing a novel and effective treatment for T2DM patients with an improved safety profile in relation to that currently available

Liver fat as risk factor of hepatic and cardiometabolic diseases

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive accumulation of fat in the liver that can progress to liver inflammation (non-alcoholic steatohepatitis [NASH]), liver fibrosis, and cirrhosis. Although most efforts for drug development are focusing on the treatment of the latest stages of NAFLD, where significant fibrosis and NASH are present, findings from studies suggest that the amount of liver fat may be an important independent risk factor and/or predictor of development and progression of NAFLD and metabolic diseases. In this review, we first describe the current tools available for quantification of liver fat in humans and then present the clinical and pathophysiological evidence that link liver fat with NAFLD progression as well as with cardiometabolic diseases. Finally, we discuss current pharmacological and non-pharmacological approaches to reduce liver fat and present open questions that have to be addressed in future studies

Obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate decreased activation of reward-related brain centers in response to food cues in both the fed and fasting states: A preliminary fMRI study

It remains unknown whether obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate altered activation of brain centers in response to food cues. We examined obese prediabetics (n=26) vs. obese nondiabetics (n=11) using fMRI. We also performed regression analyses on the basis of the number of MetS components per subject. Obese individuals with prediabetes have decreased activation of the reward-related putamen in the fasting state and decreased activation of the salience- and reward-related insula after eating. Obese individuals with more components of MetS demonstrate decreased activation of the putamen while fasting. All these activations remain significant when corrected for BMI, waist circumference (WC), HbA1c and gender. Decreased activation in reward-related brain areas between obese individuals is more pronounced in subjects with prediabetes and MetS. Prospective studies are needed to quantify their contributions to the development of prediabetes/MetS and to study whether these conditions may predispose to the exacerbation of obesity and the development of comorbidities over time

Regulation of mouse hepatic genes in response to diet induced obesity, insulin resistance and fasting induced weight reduction

BACKGROUND: Obesity is associated with insulin resistance that can often be improved by caloric restriction and weight reduction. Although many physiological changes accompanying insulin resistance and its treatment have been characterized, the genetic mechanisms linking obesity to insulin resistance are largely unknown. We used DNA microarrys and RT-PCR to investigate significant changes in hepatic gene transcription in insulin resistant, diet-induced obese (DIO)-C57/BL/6J mice and DIO-C57/BL/6J mice fasted for 48 hours, whose weights returned to baseline levels during these conditions. RESULTS: Transcriptional profiling of hepatic mRNA revealed over 1900 genes that were significantly perturbed between control, DIO, and fasting/weight reduced DIO mice. From this set, our bioinformatics analysis identified 41 genes that rigorously discriminate these groups of mice. These genes are associated with molecular pathways involved in signal transduction, and protein metabolism and secretion. Of particular interest are genes that participate in pathways responsible for modulating insulin sensitivity. DIO altered expression of genes in directions that would be anticipated to antagonize insulin sensitivity, while fasting/ weight reduction partially or completely normalized their levels. Among these discriminatory genes, Sh3kbp1 and RGS3, may have special significance. Sh3kbp1, an endogenous inhibitor of PI-3-kinase, was upregulated by high-fat feeding, but normalized to control levels by fasting/weight reduction. Because insulin signaling occurs partially through PI-3-kinase, increased expression of Sh3kbp1 by DIO mice may contribute to hepatic insulin resistance via inhibition of PI-3-kinase. RGS3, a suppressor of G-protein coupled receptor generation of cAMP, was repressed by high-fat feeding, but partially normalized by fasting/weight reduction. Decreased expression of RGS3 may augment levels of cAMP and thereby contribute to increased, cAMP-induced, hepatic glucose output via phosphoenolpyruvate carboxykinase (PCK1), whose mRNA levels were also elevated. CONCLUSION: These findings demonstrate that hepatocytes respond to DIO and weight reduction by controlling gene transcription in a variety of important molecular pathways. Future studies that characterize the physiological significance of the identified genes in modulating energy homeostasis could provide a better understanding of the mechanisms linking DIO with insulin resistance

Circulating Irisin Levels Are Not Affected by Coffee Intake: A Randomized Controlled Trial

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 NCT0030509