👤 Michael J Litt

The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity. Show less

Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. We aimed to characterize cardiac morphology and function as well as tissue Na+ content in humans with mutations in POMC and MC4R genes. A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause, and 12 normal weight controls) underwent cardiac magnetic resonance (CMR) imaging and 23Na-MRI. Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) than nonmonogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. Subcutaneous fat and skin Na+ content was significantly higher in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control groups. Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA, and stored more Na+ within the subcutaneous fat tissue than nonmonogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function and tissue Na+ storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients. Show less

Energy stores in fat tissue are determined in part by the activity of hypothalamic neurones expressing the melanocortin-4 receptor (MC4R). Even a partial reduction in MC4R expression levels in mice, rats or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. The MC4R is a G protein-coupled receptor that signals efficiently through Gα Show less

Like most homeostatic systems, adiposity in mammals is defended between upper and lower boundary conditions. While leptin and melanocortin-4 receptor (MC4R) signaling are required for defending energy set point, mechanisms controlling upper and lower homeostatic boundaries are less well understood. In contrast to the MC4R, deletion of the MC3R does not produce measurable hyperphagia or hypometabolism under normal conditions. However, we demonstrate that MC3R is required bidirectionally for controlling responses to external homeostatic challenges, such as caloric restriction or calorie-rich diet. MC3R is also required for regulated excursion from set point, or rheostasis, during pregnancy. Further, we demonstrate a molecular mechanism: MC3R provides regulatory inputs to melanocortin signaling, acting presynaptically on agouti-related protein neurons to regulate γ-aminobutyric acid release onto anorexigenic MC4R neurons, exerting boundary control on the activity of MC4R neurons. Thus, the MC3R is a critical regulator of boundary controls on melanocortin signaling, providing rheostatic control on energy storage. Show less