Increased insulin sensitivity and responsiveness of glucose metabolism in adipocytes from female versus male rats.

Abstract

This study was undertaken to examine whether there were sex-associated differences in the action of insulin on glucose metabolism in adipocytes. Insulin binding and the dose-response curves for glucose transport (assessed by measuring the cellassociated radioactivity after 15-s incubation with 50 ;&M 16-'4Clglucose) and [U-'4Cjglucose (5 mM) metabolism into CO2 and lipids were compared in retroperitoneal adipocytes from age-matched (84 d) male and female rats. In addition, the activity of fatty acid synthetase, one of the key lipogenic enzymes, was determined. Fat cell size was not significantly larger in females than in males (0.238 vs. 0.209 jig lipid per cell). At insulin concentrations < 1.6 nM, adipocytes from females bound significantly more insulin than did adipocytes from males, due to an increased apparent affinity of the receptors for insulin. Accordingly, the sensitivity of glucose transport to insulin was greater in females than in males: insulin concentration eliciting half-maximal stimulation (ED50) = 0.19 nM vs. 0.41 nM. At maximal insulin stimulation the rates of glucose transport (12 times the basal values) were similar in the two sexes. In contrast, the maximal effect of insulin on glucose conversion to CO2 plus lipids was much greater in the adipocytes from females than males (increment over basal: 472 vs. 249 nmol/106 cells per 2 h). Fatty acid synthesis contributed -40% of the incremental difference between the two types of adipocytes, while glyceride-glycerol synthesis contributed <10%. The insulin dose-response curves for adipocytes from females were shifted to the left for all the metabolic pathways investigated. The mean ED50 for total glucose metabolism in females was 50% of that in males (0.07 nM vs. 0.15 nM). Marked sex-associated differences in the action of insulin on glucose metabolism were also observed in subcutaneous inguinal adipocytes (increment over basal: 137 and 56 nmol/106 cells per 2 h, ED50 = 0.13 nM and 0.30 nM in females and males, respectively). The intracellular capacity to metabolize glucose through the fatty acid synthesis pathway, as assessed by FAS activity, was higher in adipocytes from females than in those from males and was greater in retroperitoneal than in i guinal adipocytes. Furthermore, by plotting the individual data, a highly significant correlation (r = 0.92, P < 0.001) was found between the absolute effect of insulin on glucose metabolism at maximal stimulation and the fatty acid synthetase activity of the cells.These results indicate that the response of glucose metabolism to insulin in adipocytes from female as compared with male rats is characterized by two main features: (a) an increased sensitivity primarily due to an increase in insulin binding, and (b) an increased responsiveness closely associated with a postreceptor increase in the lipogenic capacity of the cell. These findings might be relevant to the differential disposition of male and female rats to develop fatness.

Differential regulation of adipose tissue glucose transporters in genetic obesity (fatty rat). Selective increase in the adipose cell/muscle glucose transporter (GLUT 4) expression.

“…For each experiment, subcutaneous inguinal adipose tissues, the only fat depots to be developed in young rats, were removed from several animals and pooled according to the rat genotype. Adipose cells were isolated by the collagenase method of Rodbell (17) and glucose transport was measured by using 6 14C glucose (50,uM), as previously described (18). Adipose cell size was determined by a microphotographic method (19).…”

Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control

“…Human 1,2 as well as animal studies [3][4][5][6][7] demonstrate less severe obesity-related metabolic disorders including peripheral tissue insulin resistance and dyslipidemia (i.e., the components of metabolic syndrome), and/or later onset of these adverse phenotypes in female than in male subjects. However, mechanisms underlying a relatively low susceptibility of females to metabolic syndrome remain largely unknown.…”

“…However, studies in humans [38][39][40] as well as in mice 19 suggest that lower adipose tissue macrophage infiltration 19 and/or smaller fat cell size 19,40 in female subjects could contribute to the sex differences in propensity to the disorders of the metabolic syndrome. In this study performed in mice, we tested a hypothesis that because of a higher stimulation of lipogenesis and a stronger antilipolytic effect of insulin in female adipocytes, especially those in gWAT, 4,7 (1) prolonged HF feeding may eventually result in larger fat cells in female than in male animals, and that (2) glycemic control may be less affected by excessive adiposity in female than in male mice, even in the presence of larger adipocytes in the females. During the course of a long-term (35 weeks) HF feeding, body weights of male and female mice reached their maxima at a similar level.…”

Effects of insulin and norepinephrine on glucose transport and metabolism in rat brown adipocytes

“…However the isolated brown adipocytes are metabolically much more active than the isolated white adipocytes. Indeed, in the absence or presence of insulin, the amount of glucose oxidized or incorporated into fatty acids, is 2-30-fold higher in brown adipocytes than in white adipocytes [18,26,271. In brown adipocytes the activity of lipogenesis is very high, and lactate production represents a large proportion of the amount of glucose utilized [26,28,29].…”