beta 3-Adrenergic receptors (beta 3-ARs) are expressed predominantly in white and brown adipose tissue, and beta 3-selective agonists are potential anti-obesity drugs. However, the role of beta 3-ARs in normal physiology is unknown. To address this issue, homologous recombination was used to generate mice that lack beta 3-ARs. This was accomplished by direct injection of a DNA-targeting construct into mouse zygotes. Twenty-three transgenic mice were generated, of which two had targeted disruption of the beta 3-AR gene. Mice that were homozygous for the disrupted allele had undetectable levels of intact beta 3-AR mRNA, as assessed by RNase protection assay and Northern blotting, and lacked functional beta 3-ARs, as demonstrated by complete loss of beta 3-agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis. beta 3-AR-deficient mice had modestly increased fat stores (females more than males), indicating that beta 3-ARs play a role in regulating energy balance. Importantly, beta 1 but not beta 2-AR mRNA levels up-regulated in white and brown adipose tissue of beta 3-AR-deficient mice (brown more than white), strongly implying that beta 3-ARs mediate physiologically relevant signaling under normal conditions and that "cross-talk" exists between beta 3-ARs and beta 1-AR gene expression. Finally, acute treatment of normal mice with CL 316,243 increased serum levels of free fatty acids (FFAs) (3.2-fold) and insulin (140-fold), increased energy expenditure (2-fold), and reduced food intake (by 45%). These effects were completely absent in beta 3-AR-deficient mice, proving that the actions of CL are mediated exclusively by beta 3-ARs. beta 3-AR-deficient mice should be useful as a means to a better understanding of the physiology and pharmacology of beta 3-ARs.
Preadipocytes secrete several WNT family proteins that act through autocrine/paracrine mechanisms to inhibit adipogenesis. The activity of WNT ligands is often decreased by secreted frizzled-related proteins (SFRPs). Sfrp5 is strongly induced during adipocyte differentiation and increases in adipocytes during obesity, presumably to counteract WNT signaling. We tested the hypothesis that obesity-induced Sfrp5 expression promotes the development of new adipocytes by inhibiting endogenous suppressors of adipogenesis. As predicted, mice that lack functional SFRP5 were resistant to diet-induced obesity. However, counter to our hypothesis, we found that adipose tissue of SFRP5-deficient mice had similar numbers of adipocytes, but a reduction in large adipocytes. Transplantation of adipose tissue from SFRP5-deficient mice into leptin receptor-deficient mice indicated that the effects of SFRP5 deficiency are tissue-autonomous. Mitochondrial gene expression was increased in adipose tissue and cultured adipocytes from SFRP5-deficient mice. In adipocytes, lack of SFRP5 stimulated oxidative capacity through increased mitochondrial activity, which was mediated in part by PGC1α and mitochondrial transcription factor A. WNT3a also increased oxygen consumption and the expression of mitochondrial genes. Thus, our findings support a model of adipogenesis in which SFRP5 inhibits WNT signaling to suppress oxidative metabolism and stimulate adipocyte growth during obesity.
3-Adrenergic receptors (3-ARs) are expressed predominantly on white and brown adipocytes, and acute treatment of mice with CL 316,243, a potent and highly selective 3-AR agonist, produces a 2-fold increase in energy expenditure, a 50 -100-fold increase in insulin levels, and a 40 -50% reduction in food intake. Recently, we generated gene knockout mice lacking functional 3-ARs and demonstrated that each of these responses were mediated exclusively by 3-ARs. However, the tissue site responsible for producing these actions is unknown. In the present study, genetically engineered mice were created in which 3-ARs are expressed exclusively in white and brown adipocytes (WAT؉BAT-mice), or in brown adipocytes only (BAT-mice). This was accomplished by injecting tissue-specific 3-AR transgenic constructs into mouse zygotes homozygous for the 3-AR knockout allele. Control, knockout, WAT؉BAT, and BAT-mice were then treated acutely with CL, and the effects on various parameters were assessed. As previously observed, all effects of CL were completely absent in gene knockout mice lacking 3-ARs. The effects on O 2 consumption, insulin secretion, and food intake were completely rescued with transgenic re-expression of 3-ARs in white and brown adipocytes (WAT؉BAT-mice), demonstrating that each of these responses is mediated exclusively by 3-ARs in white and/or brown adipocytes, and that 3-ARs in other tissue sites were not required. Importantly, transgenic re-expression of 3-ARs in brown adipocytes only (BAT-mice) failed to rescue, in any way, CL-mediated effects on insulin levels and food intake and only minimally restored effects on oxygen consumption, indicating that any effect on insulin secretion and food intake, and a full stimulation of oxygen consumption required the presence of 3-ARs in white adipocytes. The mechanisms by which 3-AR agonist stimulation of white adipocytes produces these responses are unknown but may involve novel mediators not previously known to effect these processes.Obesity is a prevalent condition frequently associated with diabetes, hypertension, and cardiovascular disease. Because available treatments are minimally effective, substantial efforts have been directed toward the discovery of new, effective, anti-obesity drugs. The 3-adrenergic receptor (3-AR) 1 represents one of a number of potential anti-obesity drug targets for which selective agonists have been developed (1-3). The 3-AR is encoded by a distinct gene that is expressed predominantly in white and brown adipocytes (4 -7), important sites for energy storage and energy expenditure, respectively. Selective activation of 3-ARs leads to marked increases in triglyceride breakdown (lipolysis) and energy expenditure (1-3), and long term treatment of obese rodents with 3-selective agonists reduces fat stores and improves obesity-induced insulin resistance (1-3). Thus, 3-selective agonists are promising anti-obesity compounds.Acute treatment of rodents with 3-selective agonists causes a number of diverse metabolic effects in...
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