Publications

CONTEXT

The increasing prevalence of obesity is a major public health concern. Physical activity may promote weight and body fat loss.

OBJECTIVE

To examine the effects of exercise on total and intra-abdominal body fat overall and by level of exercise.

DESIGN

Randomized controlled trial conducted from 1997 to 2001.

SETTING AND PARTICIPANTS

A total of 173 sedentary, overweight (body mass index > or =24.0 and >33% body fat), postmenopausal women aged 50 to 75 years who were living in the Seattle, Wash, area.

INTERVENTION

Participants were randomly assigned to an intervention consisting of exercise facility and home-based moderate-intensity exercise (n = 87) or a stretching control group (n = 86).

MAIN OUTCOME MEASURE

Changes in body weight and waist and hip circumferences at 3 and 12 months; total body, intra-abdominal, and subcutaneous abdominal fat at 12 months.

RESULTS

Twelve-month data were available for 168 women. Women in the exercise group participated in moderate-intensity sports/recreational activity for a mean (SD) of 3.5 (1.2) d/wk for 176 (91) min/wk. Walking was the most frequently reported activity. Exercisers showed statistically significant differences from controls in baseline to 12-month changes in body weight (-1.4 kg; 95% confidence interval [CI], -2.5 to -0.3 kg), total body fat (-1.0%; 95% CI, -1.6% to -0.4%), intra-abdominal fat (-8.6 g/cm2; 95% CI, -17.8 to 0.9 g/cm2), and subcutaneous abdominal fat (-28.8 g/cm2); 95% CI, -47.5 to -10.0 g/cm2). A significant dose response for greater body fat loss was observed with increasing duration of exercise.

CONCLUSIONS

Regular exercise such as brisk walking results in reduced body weight and body fat among overweight and obese postmenopausal women.

Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity described to date. There are still conflicting data regarding the overall prevalence of such mutations in obesity and limited information is available on the functional defects caused by most obesity-associated MC4R mutations. We report here the screening for mutations in the coding region of the MC4R of a new cohort of 172 patients presenting with severe childhood obesity and a family history of obesity. Three heterozygous MC4R mutations (Ser127Leu, Ala244Glu and Pro299His) were found in three patients of this cohort (1.74%), confirming that such mutations are implicated in a significant number of childhood obesity cases. A functional analysis of these mutant receptors, in addition to 11 other childhood obesity-associated MC4R mutations, indicates that they all alter the activation of the receptor by the endogenous agonist alpha-MSH. To further examine the functional defects caused by childhood obesity-associated MC4R mutations, we developed a novel, sensitive technique to quantitatively analyze the effect of a mutation on MC4R cell surface expression. Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations. We demonstrate that 81.3% of childhood obesity-associated heterozygous MC4R mutations lead to intracellular retention of the receptor. This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition.

The relative importance of the cytokine milieu versus cytolytic T lymphocyte-associated antigen 4 (CTLA-4) and T cell receptor signal strength on T cell differentiation remains unclear. Here we have generated mice deficient for signal transducer and activator of transcription 6 (STAT6) and CTLA-4 to determine the role of CTLA-4 in cytokine-driven T cell differentiation. CTLA-4-deficient T cells bypass the need for STAT6 in the differentiation of T helper type 2 (T(H)2) cells. T(H)2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of T(H)2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-kappaB. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent T(H)2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.

Careful histopathological evaluation has shown the traditionally clinical diagnosis of idiopathic interstitial pneumonia to be more heterogeneous than once thought. Its subclassification, based on clinicopathological criteria, has important therapeutic and prognostic implications. The most important distinction is the presence of usual interstitial pneumonia, the histopathological pattern seen in idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis has a worse response to therapy and prognosis. New insight into the pathophysiology of idiopathic pulmonary fibrosis suggests a distinctly fibroproliferative process, and antifibrotic therapies show promise. Although the clinical and radiographic diagnosis of idiopathic pulmonary fibrosis can be made confidently in some cases, many patients require surgical lung biopsy to determine their underlying histopathological pattern. A structured, clinicopathological approach to the diagnosis of idiopathic interstitial pneumonia, with particular attention to the identification of idiopathic pulmonary fibrosis, ensures proper therapy, enhances prognosis, and allows for further investigation of therapies aimed at the distinct pathophysiology.