The development of society and improvements in living standards have led to an increasing prevalence of metabolic diseases such as obesity, type 2 diabetes, and hyperlipidemia, among which glucolipid metabolic disorders are key features of metabolic diseases (Fang et al., 2022). The harm of glucolipid metabolic disorders lies in prolonged abnormalities in blood glucose and lipid levels, causing damage to cells throughout the body and resulting in gradual functional decline (Di et al., 2019). Autophagy is the process by which part of the cytoplasm and organelles are encapsulated into autophagosomes and transported to lysosomes for degradation, removing damaged or aging organelles and maintaining basic energy balance (Rubinsztein et al., 2012). Disruption of autophagy is closely associated with the onset and progression of metabolic diseases such as type 2 diabetes, obesity, and dyslipidemia (Lin et al., 2021). Earlier studies on the correlation between autophagy and metabolic function focused mainly on peripheral metabolic tissues, such as the liver, skeletal muscle, pancreas, and adipocytes. As understanding of the hypothalamus's role in regulating eating, body weight, and energy balance deepens, hypothalamic autophagy has gradually gained attention. Studies have shown that the hypothalamus is quickly affected by excessive peripheral lipids (P S et al., 2016). Short-term high-fat diets (HFD) induce chaperone-mediated autophagy (CMA) in the hypothalamus, while long-term HFD leads to chronic ER stress and low-grade inflammation in the hypothalamus, damaging CMA and further impairing its role in regulating energy metabolism (M et al., 2020). In mice with obesity induced by long-term HFD, the protein levels of Atg7 and Atg 5 in the hypothalamic arcuate nucleus were significantly reduced, and the LC3-II/LC3-I ratio, reflecting autophagy levels, decreased, indicating altered hypothalamic autophagy in diet-induced obese mice (Qingyuan and Dongsheng, 2011). Moreover, HFD also reduces hypothalamic sensitivity to peripheral hormones, decreases the excitability of efferent neurons, impairs function, disrupts signaling, induces ER stress, and alters autophagy, leading to glucolipid metabolic disorders and eventually the development of metabolic diseases (Ashby and Tepikin, 2001).

The most closely monitored biomarkers associated with obesity are currently leptin (Martin G Jr et al., 2010; Roberto and Christian, 2012; Vanessa et al., 2021). Leptin, primarily derived from adipose tissue, plays a pivotal role in regulating glucose and lipid metabolism through integrated central and peripheral modulation, reducing food intake, increasing energy expenditure, and lowering blood glucose levels (María F et al., 2019). Imbalances in leptin regulation manifest as leptin deficiency and leptin resistance. Leptin resistance refers to the insensitivity of tissue to leptin, ultimately preventing leptin from exerting its regulatory effects through the central nervous system, leading to the onset of obesity and further promoting leptin secretion, exacerbating hyperleptinemia, and significantly associating with hypertension, obesity, type 2 diabetes, and other related disorders of glucose and lipid metabolism (Lanaspa et al., 2018; Martin G Jr et al., 2010). The leptin receptor (leptin receptor, LepRb) is highly expressed in the brain, particularly in the AgRP and POMC neurons of the hypothalamus (Aragonès et al., 2016). Current research findings indicate abnormalities in hypothalamic neurons that play a role in metabolic regulation (such as POMC and AgRP neurons) and proteins related to leptin signaling (such as SOCS3, STAT3, and PTP1B, etc.) (María F et al., 2019), hypothalamic inflammation (Thaler et al., 2011), hyperleptinemia (causing blood-brain barrier transport disorders) (Xiaohuan and Ning, 2009; Zhao et al., 2019), ER stress (Pagliassotti et al., 2016), and abnormal autophagy (Wenying et al., 2012) are phenomena accompanying central leptin resistance. However, the mechanisms underlying leptin resistance have not been fully elucidated, and strategies to overcome leptin resistance currently focus on mechanisms within the hypothalamus (Pan et al., 2014). Leptin centrally regulates appetite and satiety to reduce energy intake, inhibiting appetite, promoting energy balance, and reducing fat accumulation (Bates and Jr, 2003; Valos et al., 2018). Leptin activates POMC neurons in the hypothalamus to suppress appetite through the production of α-MSH (Junewoo et al., 2022) and regulates glucose metabolism (Jennifer W et al., 2010; Lihong et al., 2009; Mark A et al., 2015) and lipid metabolism (Sebastien M et al., 2015; Yi et al., 2016). Knockdown of autophagy proteins can affect leptin signaling transduction and alter leptin sensitivity. When autophagy proteins in hypothalamic POMC neurons are knocked out, leptin sensitivity is reduced, primarily due to damage to leptin signaling via STAT3 (Bates et al., 2003). POMC neuron-specific Atg7 knockout mice show reduced leptin sensitivity in neurons, specifically exhibiting impaired responses of POMC neurons to leptin. The ability of leptin to inhibit food intake after fasting is weakened in Atg7△POMC mice, while leptin-induced signal transduction and STAT3 phosphorylation are also damaged (Wenying et al., 2012).

The interplay of multiple factors confers complexity to glucose and lipid metabolic disorders, and single interventions targeting hyperglycemia or hyperlipidemia alone cannot effectively ameliorate multiple metabolic disturbances (Fang et al., 2022). Therefore, pharmacotherapy often employs the combination of hypoglycemic and lipid-lowering drugs. In contrast, traditional Chinese medicine (TCM) often uses natural products and compound prescriptions to regulate the liver, strengthen the spleen, and resolve turbidity to treat patients. Clinical and animal experimental studies have demonstrated that TCM compound prescriptions and their individual components are significantly effective in regulating glucose and lipid metabolic disorders. Professor Guo, from the perspective of the core pathogenic concept of “turbidity" in TCM, has developed a representative TCM formula—Fufang Zhenzhu Tiaozhi Capsule (FTZ)—based on the comprehensive prevention and treatment concept of “regulating the liver, activating the pivot, and resolving turbidity". FTZ has shown superior clinical efficacy with no significant toxic side effects, broad therapeutic targets, and marked improvements in patients' symptoms and quality of life (Guo, 2017; Guo et al., 2011; Tang et al., 2011). FTZ is composed of eight TCM ingredients, including Buddha's hand, Eucommia ulmoides, Atractylodes macrocephala, Ligustrum lucidum, Coptis chinensis, Salvia miltiorrhiza, Notoginseng, and Cirsium japonicum, with major active components including berberine hydrochloride, oleanolic acid, total saponins of Notoginseng, schisandrin, and ginsenosides (Guo et al., 2011; Zhong et al., 2012). “Tiaozhi” refers to regulating body fat levels, including blood lipids and visceral fat (Chen et al., 2018; Guo, J. et al., 2011). Clinical trials conducted over many years have demonstrated that FTZ is effective in more than 95 % of over 3000 dyslipidemic patients (Guo, J. et al., 2011). Previous studies have shown that FTZ regulates glucose and lipid metabolism by reducing serum cholesterol (Guo et al., 2011; Hong-Xia et al., 2011), improving ER stress (Zhiquan et al., 2016), and alleviating insulin resistance (Hu et al., 2014), and it has shown good therapeutic effects on patients with diabetes, hyperlipidemia, and atherosclerosis. BBR can penetrate the blood-brain barrier and act directly on neuronal cells, exerting neuroprotective effects by ameliorating oxidative stress, triggering autophagy, inhibiting apoptosis and reducing neuroinflammation (Kim et al., 2014; Liang et al., 2017; Mak et al., 2014; Shan et al., 2011). It has been found that FTZ and its active component BBR can improve hypothalamic inflammation and leptin resistance, thereby ameliorating systemic glucose and lipid metabolic disorders, but the underlying mechanisms remain unclear. To explore the regulatory mechanisms of FTZ and its active component BBR on hypothalamic ERS and leptin resistance in high-fat diet-induced glucose and lipid metabolic disorders, we conducted studies using a diet-induced obesity (DIO) rat model.