No abstract

In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2-α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other's surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis.

The aromatase-knockout (ArKO) mouse provides a useful model to examine the role that estrogens play in development and homeostasis in mammals. Lacking a functional Cyp19 gene, which encodes aromatase, the ArKO mouse cannot synthesize endogenous estrogens. We examined the adipose depots of male and female ArKO mice, observing that these animals progressively accumulate significantly more intraabdominal adipose tissue than their wild-type (WT) littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared with WT controls, as were elevated insulin levels, although blood glucose levels were unchanged. Associated with these changes, a striking accumulation of lipid droplets was observed in the livers of ArKO animals. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.estrogen deficiency ͉ obesity ͉ insulin ͉ cholesterol ͉ leptin A romatase is encoded by the Cyp19 gene and catalyzes the final step in the biosynthesis of C 18 estrogens from C 19 steroids. The sexually dimorphic distribution of adipose tissue in humans has implicated sex steroids in the regulation of adiposity and distribution of fat depots. Thus, whereas premenopausal women tend to have a lower body or gynoid distribution of fat, men and postmenopausal women tend to have an upper body or android distribution of fat. This phenotype is associated with a greater risk of insulinresistant diabetes, cardiovascular disease, and breast cancer (1). Estrogen insufficiency is thought to be largely responsible for the increase in adiposity during menopause because postmenopausal women who receive estrogen replacement therapy do not display the characteristic abdominal weight gain pattern usually associated with menopause (2). The role that estrogens play in lipid metabolism in the body is also highlighted by the fact that individuals of both sexes with natural mutations of the gene encoding aromatase, the enzyme responsible for estrogen biosynthesis, develop truncal obesity, insulin resistance, hypercholesterolemia, and hypertriglyceridemia (3-6).We have recently developed a mouse model of estrogen insufficiency by targeted disruption of the aromatase gene: the aromatase-knockout (ArKO) mouse (7). In the course of these studies, we observed that the animals displayed a progressive increase in adiposity as compared with wild-type (WT) littermates. The aim of the present investigation was to characterize the obese phenotype of these animals in the expectation that this would throw light on the role of estrogens in lipid homeostasis. Materials and MethodsMice. ArKO mice were generated by disrupting the Cyp19 gene as described (7). Heterozygous males and fema...