Abstract
Beta-3 adrenergic receptor activation via exercise or CL316,243 (CL) induces white adipose tissue (WAT) browning, improves glucose tolerance, and reduces visceral adiposity. Our aim was to determine if sex or adipose tissue depot differences exist in response to CL. Daily CL injections were administered to diet-induced obese male and female mice for two weeks, creating four groups: male control, male CL, female control, and female CL. These groups were compared to determine the main and interaction effects of sex (S), CL treatment (T), and WAT depot (D). Glucose tolerance, body composition, and energy intake and expenditure were assessed, along with perigonadal (PGAT) and subcutaneous (SQAT) WAT gene and protein expression. CL consistently improved glucose tolerance and body composition. Female PGAT had greater protein expression of the mitochondrial uncoupling protein 1 (UCP1), while SQAT (S, p < 0.001) was more responsive to CL in increasing UCP1 (S×T, p = 0.011) and the mitochondrial biogenesis induction protein, PPARγ coactivator 1α (PGC1α) (S×T, p = 0.026). Females also displayed greater mitochondrial OXPHOS (S, p < 0.05) and adiponectin protein content (S, p < 0.05). On the other hand, male SQAT was more responsive to CL in increasing protein levels of PGC1α (S×T, p = 0.046) and adiponectin (S, p < 0.05). In both depots and in both sexes, CL significantly increased estrogen receptor beta (ERβ) and glucose-related protein 75 (GRP75) protein content (T, p < 0.05). Thus, CL improves systemic and adipose tissue-specific metabolism in both sexes; however, sex differences exist in the WAT-specific effects of CL. Furthermore, across sexes and depots, CL affects estrogen signaling by upregulating ERβ.
Highlights
Young females are protected against metabolic dysfunction compared to age-matched males and postmenopausal females [1,2,3,4]
high-fat diet (HFD)-induced obesity and insulin resistance among females [53], we investigated the depot-specific adipose tissue mitochondrial profile between sexes, and compared sexes for the effect of CL on these mitochondrial parameters
CL significantly increased the ERβ to ERα ratio in both white adipose tissue (WAT) depots, and in both sexes, (T, p = 0.012). These results demonstrate that: (1) PGAT and SQAT brown well in females, whereas in males, PGAT is resistant to the effects of CL, compared to SQAT, and (2) ERβ is upregulated in a sex- and depot-independent manner by chronic adrenergic activation in WAT
Summary
Young females are protected against metabolic dysfunction (e.g., type II diabetes, obesity, cardiovascular disease) compared to age-matched males and postmenopausal females [1,2,3,4]. Adipose tissue dysfunction has been linked to numerous metabolic diseases [12,13,14], is heavily influenced by E2 [15,16,17], and is the major site of E2 synthesis in males and postmenopausal females [18,19]. These sex differences in adipose tissue physiology likely contribute to the sexual dimorphism observed in metabolic disease [1,20]. In addition to WAT, mammals contain smaller mitochondrial-rich depots of brown adipose tissue (BAT), the primary site of non-shivering thermogenesis
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