Adipose tissue is a key regulator of whole-body metabolic fitness because of its role in controlling insulin sensitivity. Obesity is associated with hypertrophic adipocytes with impaired glucose absorption, a phenomenon existing in the ultrarare monogenic disorder Alström syndrome consisting of severe insulin resistance. Inactivation of ALMS1 directly inhibits insulin-mediated glucose absorption in the white adipose tissue and induces severe insulin resistance, which leads to type 2 diabetes, accelerated nonalcoholic liver disease, and fibrosis. These phenotypes were reversed by specific adipocyte-ALMS1 reactivation in vivo. Subsequently, ALMS1 was found to bind to protein kinase C-α (PKCα) in the adipocyte, and upon insulin signaling, PKCα is released from ALMS1. α-Helices in the kinase domain of PKCα were therefore screened to identify a peptide sequence that interfered with the ALMS1-PKCα protein interaction. When incubated with cultured human adipocytes, the stapled peptide termed PATAS, for Peptide derived of PKC Alpha Targeting AlmS, triggered insulin-independent glucose absorption, de novo lipogenesis, and cellular glucose utilization. In vivo, PATAS reduced whole-body insulin resistance, and improved glucose intolerance, fasting glucose, liver steatosis, and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.

中文翻译：

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PATAS 是一种一流的治疗性肽生物制剂，可在体内改善全身胰岛素抵抗和相关合并症

脂肪组织因其在控制胰岛素敏感性方面的作用而成为全身代谢适应性的关键调节剂。肥胖与葡萄糖吸收受损的肥大脂肪细胞有关，这种现象存在于由严重胰岛素抵抗组成的超罕见单基因疾病 Alström 综合征中。ALMS1 的失活直接抑制白色脂肪组织中胰岛素介导的葡萄糖吸收并诱导严重的胰岛素抵抗，从而导致 2 型糖尿病、加速的非酒精性肝病和纤维化。这些表型被体内特定的脂肪细胞-ALMS1 重新激活所逆转。随后，发现 ALMS1 与脂肪细胞中的蛋白激酶 C-α (PKCα) 结合，并且在胰岛素信号转导下，PKCα 从 ALMS1 中释放出来。因此筛选 PKCα 激酶结构域中的α-螺旋以鉴定干扰 ALMS1-PKCα 蛋白质相互作用的肽序列。当与培养的人类脂肪细胞一起孵育时，称为 PATAS 的钉合肽（用于 PKC Alpha Targeting AlmS 衍生的肽）触发了不依赖胰岛素​​的葡萄糖吸收、从头脂肪生成和细胞葡萄糖利用。在体内，PATAS 降低了全身胰岛素抵抗，并改善了啮齿动物的葡萄糖耐受不良、空腹血糖、肝脂肪变性和纤维化。因此，PATAS 代表了一种新型的一流肽，其靶向脂肪细胞以改善胰岛素抵抗及其相关合并症。对于源自 PKC Alpha Targeting AlmS 的肽，触发了不依赖胰岛素​​的葡萄糖吸收、从头脂肪生成和细胞葡萄糖利用。在体内，PATAS 降低了全身胰岛素抵抗，并改善了啮齿动物的葡萄糖耐受不良、空腹血糖、肝脂肪变性和纤维化。因此，PATAS 代表了一种新型的一流肽，其靶向脂肪细胞以改善胰岛素抵抗及其相关合并症。对于源自 PKC Alpha Targeting AlmS 的肽，触发了不依赖胰岛素​​的葡萄糖吸收、从头脂肪生成和细胞葡萄糖利用。在体内，PATAS 降低了全身胰岛素抵抗，并改善了啮齿动物的葡萄糖耐受不良、空腹血糖、肝脂肪变性和纤维化。因此，PATAS 代表了一种新型的一流肽，其靶向脂肪细胞以改善胰岛素抵抗及其相关合并症。