Obesity is a major driver of insulin resistance and a key pathological hallmark and driving factor in type 2 diabetes and the associated co-morbidities. Thus, therapeutic strategies for combating obesity, type 2 diabetes and comorbidities should ideally both promote weight loss and enhance insulin sensitivity. The potential for such strategies is exemplified by the tremendous success of glucagon-like peptide-1 (GLP-1) receptor agonists that now hold a privileged place in the management of type 2 diabetes and obesity and are having significant impact on the incidence of liver disease and cardiovascular disease. The success of GLP-1 receptor agonists can be attributed to their ability to act both in the CNS to promote satiety and weight loss and peripherally to increase pancreatic insulin secretion and to repress glucagon release and slow gastric emptying. However, it is important to recognise that GLP-1-based drugs are not effective in all individuals, and they can be accompanied by significant complications, including gastrointestinal issues and muscle wasting. The current study explores the therapeutic potential of targeting protein tyrosine phosphatases (PTPs) that act both in the CNS and in peripheral metabolic tissue to negatively regulating leptin and insulin signalling. We demonstrate that the targeting of such PTPs for proteasomal degradation using PROTACS (PROteolysis TArgeting Chimeras) and the promotion of both leptin and insulin signalling promotes weight loss, corrects hepatic steatosis and improves glucose homeostasis in high fat fed obese C57BL/6 mice without promoting muscle wasting. These studies stand to deliver the next generation of CNS and peripherally acting therapeutics that may rival GLP-1 receptor agonists in their ability to combat obesity and type 2 diabetes.