Brown adipose tissue and its therapeutic potential.

Obesity and related diseases are a major cause of human morbidity and mortality and constitute a substantial economic burden for society. Effective treatment regimens are scarce, and new therapeutic targets are needed. Brown adipose tissue, an energy-expending tissue that produces heat, represents a potential therapeutic target. Its presence is associated with low body mass index, low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Knowledge about the development and function of thermogenic adipocytes in brown adipose tissue has increased substantially in the last decade. Important transcriptional regulators have been identified, and hormones able to modulate the thermogenic capacity of the tissue have been recognized. Intriguingly, it is now clear that humans, like rodents, possess two types of thermogenic adipocytes: the classical brown adipocytes found in the interscapular brown adipose organ and the so-called beige adipocytes primarily found in subcutaneous white adipose tissue after adrenergic stimulation. The presence of two distinct types of energy-expending adipocytes in humans is conceptually important because these cells might be stimulated and recruited by different signals, raising the possibility that they might be separate potential targets for therapeutic intervention. In this review, we will discuss important features of the energy-expending brown adipose tissue and highlight those that may serve as potential targets for pharmacological intervention aimed at expanding the tissue and/or enhancing its function to counteract obesity.

Mc2 receptor knockdown modulates differentiation and lipid composition in adipocytes.

The melanocortin system is involved in central and peripheral regulation of energy homeostasis. In adipocytes, the melanocortin 2 receptor (MC2R) transmits ACTH-dependent signaling and its expression rises substantially during adipocyte differentiation. An in vitro system of retrovirally expressed shRNA directed against Mc2r mRNA in 3T3-L1 cells was established and effects of Mc2r knockdown (kd) in comparison to cells expressing non-targeting shRNA (control) were explored in differentiated adipocytes. Morphology, gene expression, lipolysis and fatty acid composition were analyzed. While gross morphology was unchanged extractable amount of lipids was reduced to 70-80% in kd cell lines (p<0.01). Moreover, expression changes of Pparγ2, aP2, and Pref1 indicated reduced differentiation in Mc2r kd cells. Intriguingly, not only ACTH, but also norepinephrine stimulated lipolysis were substantially reduced demonstrating functional significance of MC2R for general lipolysis pathway. Analysis of fatty acid composition in triglyceride and phospholipid fractions showed a lowered ratio of C16:1/C16:0 and C18:1/C18:0, but increased concentrations of arachidonic acid upon Mc2r knockdown. Reduction of mono-unsaturated fatty acids (MUFAs) was associated with lower expression of stearoyl-Coenzyme A desaturase 1 and 2 in kd cells (21 ± 8% vs. 100 ± 13%, p=0.01 and 32 ± 3% vs. 100 ± 15%, p=0.046). Conversely, high doses of ACTH resulted in gene expression changes, mirroring Mc2r knockdown (higher Pparγ2, Scd1, Hsl expression). MC2R plays an important role for regular lipolytic function and lipid composition in 3T3-L1 adipocytes. Of interest, desaturase expression was reduced and MUFA content accordingly altered in kd cells.

Sepsis and cardiomyopathy as rare clinical manifestations of pheochromocytoma--two case report studies.

The clinical manifestation of pheochromocytomas is highly variable and can closely resemble numerous clinical conditions. Here, we report on two cases of patients with pheochromocytoma, which manifested as sepsis or cardiomyopathy. The first patient initially presented with bacterial urosepsis due to klebsiella oxytoca. Despite effective antibiotic therapy, the patient developed recurring fever accompanied by hypertension. The inconsistency between therapy-refractory hypertension and fever indicated the possibility of excessive catecholamine production. In the second case, the patient presented with a suspected ST-segment elevation myocardial infarction accompanied by E. coli sepsis and a previously undiagnosed unilateral tumor mass of the adrenal gland. Severely impaired myocardial contraction of the apical anterior and inferior regions without significant coronary artery disease was consistent with the Takotsubo cardiomyopathy, a known transient functional myocardial complication associated with pheochromocytoma. Both patients were diagnosed with unilateral pheochromocytoma. Following pre-operative antihypertensive therapy, both patients were cured by surgery and still remain free of disease after two years of follow-up.