Obesity is a well-known risk factor for the development of secondary complications such as type 2 diabetes. However, only a part of the obese population develops secondary metabolic disorders. Here, we identify the transcription factor retinoid-related orphan receptor gamma (RORγ) as a negative regulator of adipocyte differentiation through expression of its newly identified target gene matrix metalloproteinase 3. In vivo differentiation of adipocyte progenitor cells from Rorγ-deficient mice is enhanced and obese Rorγ−/− mice show decreased adipocyte sizes. These small adipocytes are highly insulin sensitive, leading to an improved control of circulating free fatty acids. Ultimately, Rorγ−/− mice are protected from hyperglycemia and insulin resistance in the state of obesity. In adipose stromal-vascular fraction from obese human subjects, Rorγ expression is correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity. Taken together, our findings identify RORγ as a factor, which controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. RORγ might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

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In this program, the AA-genotype of rs9939609 was associated with a higher initial body weight and did influence success of weight stabilization. Thus, emphasizing the maintenance phase during a weight reduction program might result in better success for AA-genotype carriers.

This prospective study was performed in order to establish whether improvement of endothelial function after weight reduction can be explained by a decrease of elevated asymmetric dimethyl arginine (ADMA), an inhibitor of endogenous NO-synthase (eNOS). Therefore, 21 obese subjects (BMI: 41.1±6.4 kg/m(2)) were studied at baseline and after 12 weeks of weight reduction with a very low calorie diet. Biochemical and clinical parameters of endothelial function were assessed before and after weight loss. Biochemical parameters were determined by measurement of ADMA and soluble intercellular adhesion molecule (sICAM). Clinical parameters were assessed by pulse wave analysis (PWA). Weight intervention resulted in a 21.4±6.8 kg reduction of body weight from 119.7±12.8 kg at study start to 98.3±11.6 kg at study end (p<0.001). Accordingly, biochemical markers improved under weight reduction (ADMA from 0.47±0.07 mmol/l to 0.42±0.08 mmol/l; p=0.002; ICAM from 276±42 ng/ml to 236±29 ng/ml; p<0.001). Further, clinical parameters of functional endothelial function improved with an increase of deltaRI after salbutamol inhalation from -1% before to -9% after weight reduction (p=0.02). Interestingly, improvement of endothelial function correlated with improved HOMA index only (r=-0.60, p=0.04) but not with reduced ADMA levels, improved hypertension or reduced body weight. In conclusion, weight reduction with a very low calorie diet improves endothelial function measured by pulse wave velocity. The missing correlation with ADMA suggests possible further mechanisms underlying this observed effect, for example, improvement of insulin resistance.

Aims: To compare effectiveness of a 1-year weight loss program in moderately and severely obese patients. Methods: The study sample included 311 obese patients participating in a weight loss program, which comprised a 12-week weight reduction phase (low-calorie formula diet) and a 40-week weight maintenance phase. Body weight and glucose and lipid values were determined at the beginning of the program as well as after the weight reduction and the weight maintenance phase. Participants were analyzed according to their BMI class at baseline (30-34.9 kg/m²; 35-39.9 kg/m²; 40-44.9 kg/m²; 45-49.9 kg/m²; ≥50 kg/m²). Furthermore, moderately obese patients (BMI < 40 kg/m²) were compared to severely obese participants (BMI ≥ 40 kg/m²). Results: Out of 311 participants, 217 individuals completed the program. Their mean baseline BMI was 41.8 ± 0.5 kg/m².Average weight loss was 17.9 ± 0.6%, resulting in a BMI of 34.3 ± 0.4 kg/m² after 1 year (p < 0.001). Overall weight loss was not significantly different in moderately and severely obese participants. Yet, severely obese participants achieved greater weight loss during the weight maintenance phase than moderately obese participants (-3.1 ± 0.7% vs. -1.2 ± 0.6%; p = 0.04). Improvements in lipid profiles and glucose metabolism were found throughout all BMI classes. Conclusion: 1-year weight loss intervention improves body weight as well as lipid and glucose metabolism not only in moderately, but also in severely obese individuals.