Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mol Metab. 2019 Sep;27:11-21. doi: 10.1016/j.molmet.2019.06.019. Epub 2019 Jun 22.
The sympathetic nervous system (SNS) is a key regulator of the metabolic and endocrine functions of adipose tissue. Increased SNS outflow promotes fat mobilization, stimulates non-shivering thermogenesis, promotes browning, and inhibits leptin production. Most of these effects are attributed to norepinephrine activation of the Gs-coupled beta adrenergic receptors located on the surface of the adipocytes. Evidence suggests that other adrenergic receptor subtypes, including the Gi-coupled alpha 2 adrenergic receptors might also mediate the SNS effects on adipose tissue. However, the impact of acute stimulation of adipocyte Gs and Gi has never been reported.
We harness the power of chemogenetics to develop unique mouse models allowing the specific and spatiotemporal stimulation of adipose tissue Gi and Gs signaling. We evaluated the impact of chemogenetic stimulation of these pathways on glucose homeostasis, lipolysis, leptin production, and gene expression.
Stimulation of Gs signaling in adipocytes induced rapid and sustained hypoglycemia. These hypoglycemic effects were secondary to increased insulin release, likely consequent to increased lipolysis. Notably, we also observed differences in gene regulation and ex vivo lipolysis in different adipose depots. In contrast, acute stimulation of Gi signaling in adipose tissue did not affect glucose metabolism or lipolysis, but regulated leptin production.
Our data highlight the significance of adipose Gs signaling in regulating systemic glucose homeostasis. We also found previously unappreciated heterogeneity across adipose depots following acute stimulation. Together, these results highlight the complex interactions of GPCR signaling in adipose tissue and demonstrate the usefulness of chemogenetic technology to better understand adipocyte function.
交感神经系统（SNS）是调节脂肪组织代谢和内分泌功能的关键。SNS 输出增加可促进脂肪动员、刺激非颤抖性产热、促进棕色化、抑制瘦素产生。这些作用主要归因于去甲肾上腺素激活位于脂肪细胞表面的 Gs 偶联β肾上腺素能受体。有证据表明，其他肾上腺素受体亚型，包括 Gi 偶联的α2肾上腺素能受体，也可能介导 SNS 对脂肪组织的作用。然而，急性刺激脂肪细胞 Gs 和 Gi 的影响从未被报道过。
我们利用化学遗传学的力量开发了独特的小鼠模型，允许特异性和时空刺激脂肪组织 Gi 和 Gs 信号。我们评估了这些途径的化学遗传刺激对葡萄糖稳态、脂肪分解、瘦素产生和基因表达的影响。
刺激脂肪细胞中的 Gs 信号会导致快速而持续的低血糖。这些低血糖作用继发于胰岛素释放增加，可能是由于脂肪分解增加所致。值得注意的是，我们还观察到不同脂肪组织中基因调控和体外脂肪分解的差异。相比之下，急性刺激脂肪组织中的 Gi 信号不会影响葡萄糖代谢或脂肪分解，但会调节瘦素产生。
我们的数据强调了脂肪 Gs 信号在调节全身葡萄糖稳态中的重要性。我们还发现，在急性刺激后，不同脂肪组织中存在以前未被认识到的异质性。这些结果共同强调了 GPCR 信号在脂肪组织中的复杂相互作用，并证明了化学遗传技术在更好地理解脂肪细胞功能方面的有用性。
