Palmitic acid control of ciliogenesis modulates insulin signaling in hypothalamic neurons through an autophagy-dependent mechanism

Abstract

Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.

Weizmannia coagulans BC2000 Plus Ellagic Acid Inhibits High-Fat-Induced Insulin Resistance by Remodeling the Gut Microbiota and Activating the Hepatic Autophagy Pathway in Mice

“…These findings were consistent with another study [ 23 ] in which EA plus BC2000 intervention significantly regulated autophagy and mitophagy pathways. Autophagy can play an important role in various physiological and pathological processes such as cell homeostasis, ageing, immunity, tumorigenes, and neurodegenerative diseases [ 24 ]. Studies have shown that urolithin A, a metabolite of EA in the gut, can prolong the lifespan of nematodes and improve muscle function in rodents by inducing autophagy [ 25 ].…”

Effects of the POMC System on Glucose Homeostasis and Potential Therapeutic Targets for Obesity and Diabetes

“…43 In addition, the loss of cilia and autophagy in the POMC neurons can disrupt insulin signaling, prevent insulin-dependent glucose uptake, and eventually lead to obesity and insulin resistance in mice. 45 Recently, novel molecules and mechanisms related to insulin resistance have gradually been revealed. For instance, inositolrequiring enzyme 1α (IRE1α), 46 spliced X-box binding protein 1 (XBP1s), 47 and other positive regulatory factors can activate the POMC neurons, enhance peripheral insulin sensitivity, improve glucose tolerance, inhibit liver glucose production, and thus, prevent obesity and type 2 diabetes.…”

“…Moreover, compensatory secretion of insulin leads to hyperinsulinemia, which can lead to type 2 diabetes and obesity. In recent years, studies have found that some central factors are associated with insulin resistance, such as obesity, 42 hypothalamic inflammation, 43 endoplasmic reticulum stress, 44 and the cilia and autophagy mechanism, 45 which can prevent insulin from transmitting peripheral metabolic information to the center, resulting in impaired glucose metabolism. A long-term high-fat diet (HFD) or hypothalamic inflammation can activate some inflammatory factors such as toll-like receptor-4 (TLR4), tumor necrosis factor (TNF), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB).…”

“… 43 In addition, the loss of cilia and autophagy in the POMC neurons can disrupt insulin signaling, prevent insulin-dependent glucose uptake, and eventually lead to obesity and insulin resistance in mice. 45 …”

Autophagy and the primary cilium in cell metabolism: What’s upstream?

“…Many signaling pathways emanate from the primary cilium and among these, several are engaged in the regulation of metabolism ( Pala et al, 2017 ; Anvarian et al, 2019 ; Avalos et al, 2022 ; Yang et al, 2022a ). For example, an interplay between the Hedgehog and mTORC1 pathways exist ( Larsen and Moller, 2020 ), and both are regulated by the primary cilium.…”