Preclinical pharmacological characterization of GLP-1 agonists, PPARα activators, and peripheral CB1 antagonists in the treatment of high-fat high-fructose diet–induced metabolic and neuroendocrine dysregulation

Obesity is a multifaceted metabolic disorder increasingly recognized for its impact not only on peripheral systems such as lipid and glucose metabolism but also on central nervous system (CNS) health, including neurodegenerative processes. Chronic consumption of high-fat, high-fructose diets (HFHFD) leads to systemic metabolic dysfunction characterized by insulin resistance, dyslipidemia, hepatic steatosis, and neuroinflammation, ultimately contributing to cognitive impairment and abnormal neuronal signaling, including tau pathology. Given the limited efficacy and side-effect profiles of current monotherapies, the development of multitarget pharmacological strategies that address both peripheral and central components of obesity is of paramount importance. This research studies investigates the therapeutic efficacy of two novel combination strategies involving glucagon-like peptide-1 (GLP-1) receptor agonists and cannabinoid receptor type 1 (CB1) antagonists/ PPARα agonist in a rat model of diet-induced obesity. The first approach utilizes Oleyl Hydroxytyrosol Ether (OLHHA), a novel amide derivative that acts as a PPARα activator and CB1 inhibitor, either alone or in combination with liraglutide (LIG), a centrally acting GLP-1 receptor agonist. The second strategy combines LH-21, a peripherally restricted CB1 receptor antagonist, with liraglutide to test the impact of dual peripheral-central targeting on obesity-induced pathology. Rats subjected to HFHFD developed hallmark features of metabolic syndrome, including significant weight gain, elevated triglycerides and LDL cholesterol, impaired hepatic function, and disrupted central metabolic signaling. Neurologically, these rats showed enhanced expression and phosphorylation of tau protein, indicating early neurodegenerative changes. Monotherapies with OLHHA, LH-21, or LIG led to partial improvements in metabolic markers and brain signaling pathways but were insufficient for full restoration of physiological and molecular balance. In recent investigations, combination therapies such as OLHHA+LIG and LH-21+LIG have shown superior therapeutic efficacy compared to their individual components, producing synergistic effects that address both metabolic dysfunction and central nervous system impairments. These therapies led to robust reductions in body weight that were not solely due to decreased food intake, indicating enhanced metabolic efficiency and increased energy expenditure. They also normalized plasma glucose levels, improved insulin sensitivity, and corrected dyslipidemia, as evidenced by lower circulating triglycerides, LDL cholesterol and elevated HDL cholesterol. Additionally, these treatments effectively reversed hepatic steatosis, reducing lipid accumulation in the liver and attenuating hepatic inflammation and fibrotic markers. The improvements extended to adipose tissue, where reductions in adipocyte hypertrophy and systemic inflammatory cytokines suggested a broad anti-inflammatory action. Notably, these combination treatments also produced significant central nervous system benefits. 72 Key brain regions involved in metabolic regulation and cognitive function, the hypothalamus, hippocampus, and prefrontal cortex, exhibited restored signaling pathways related to appetite control, insulin and leptin sensitivity, inflammation, and tau pathology. Restoration of hypothalamic function included normalization of neuronal insulin signaling and reduced hypothalamic gliosis, critical for long-term energy homeostasis. The hippocampus and prefrontal cortex showed decreased neuroinflammation and oxidative stress, along with improved markers of synaptic plasticity and reduced tau phosphorylation, all indicative of a neuroprotective effect. These improvements are attributable to the complementary mechanisms of the two agents: LH-21, a peripherally restricted CB1 receptor antagonist, avoided the psychiatric side effects linked with brain-penetrant CB1 blockers while effectively reducing lipogenesis, improving insulin signaling, and lowering inflammation in peripheral tissues. Liraglutide, a GLP-1 receptor agonist capable of crossing the blood-brain barrier, exerted central effects that included appetite suppression, enhanced neurogenesis, reduced microglial activation, and decreased amyloid and tau pathologies. The synergy between the peripheral actions of LH-21 and the central actions of liraglutide allows for a comprehensive approach that simultaneously addresses the systemic metabolic disturbances and the neural deficits often seen in obesity and type 2 diabetes. This integrated therapeutic strategy offers a promising avenue for treating complex metabolic-neurodegenerative disorders and highlights the potential of targeting both peripheral and central pathways to achieve sustained metabolic correction and neuroprotection without compromising patient safety. Overall, these findings underscore the therapeutic potential of multitarget pharmacological interventions that integrate peripheral metabolic modulation with central neuroendocrine regulation. The dual-action strategies not only address obesity and its metabolic complications but also exert neuroprotective effects, thereby representing a promising avenue for treating obesity and its associated neurodegenerative risks. These preclinical results provide strong justification for further investigation into such combination therapies for clinical application in human populations.