Palmitate Attenuates Insulin Signaling and Induces Endoplasmic Reticulum Stress and Apoptosis in Hypothalamic Neurons: Rescue of Resistance and Apoptosis through Adenosine 5′ Monophosphate-Activated Protein Kinase Activation

Abstract

Hypothalamic insulin signaling is essential to the maintenance of glucose and energy homeostasis. During pathological states, such as obesity and type 2 diabetes mellitus, insulin signaling is impaired. One key mechanism involved in the development of insulin resistance is lipotoxicity, through increased circulating saturated fatty acids. Although many studies have begun to determine the underlying mechanisms of lipotoxicity in peripheral tissues, little is known about the effects of excess lipids in the brain. We used a hypothalamic, neuronal cell model, mHypoE-44, to understand how the highly prevalent nonesterified fatty acid, palmitate, affects neuronal insulin signaling. Through Western blot analysis, we discerned that prolonged exposure to palmitate impairs insulin activation, as assessed by phosphorylation of Akt. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cellular insulin resistance and apoptosis in peripheral tissues. Palmitate treatment induced ER stress through a c-Jun N-terminal kinase (JNK)-dependent pathway because a selective JNK inhibitor blocked palmitate activation of the ER stress pathways eIF2 alpha and X-box binding protein-1. Interestingly, JNK inhibition did not prevent the palmitate-mediated cleaved caspase-3 increase, an apoptotic marker, or insulin signaling attenuation. However, pretreatment with the AMP kinase activator, aminoimidazole carboxamide ribonucleotide, blocked JNK phosphorylation and importantly prevented caspase-3 cleavage and restored insulin signaling during short-term exposure to palmitate. Thus, activation of AMP kinase prevents the deleterious effects of palmitate on hypothalamic neurons by inhibiting the onset of insulin resistance and apoptosis.

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

“…[26][27][28] Consistent with previous experimental observations, palmitate (500 mM) was sufficient to significantly block the effects of insulin and trigger ER stress, evidenced by the decreased phosphorylation of Akt and IRS-1, and elevated phosphorylation of PERK and eIF2a (Fig. 6D-F).…”

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

“…This suggests that chronic hyperglycemia and/or hyperlipidemia could lead to accumulation of lipids that may have deleterious effects on insulin sensitivity. This hypothesis is supported by recent studies showing that high fat feeding increases hypothalamic DAG and TAG content in mice (58) and that palmitate induces insulin resistance in the arcuate nucleus (59) and in N44 hypothalamic neurons (60). Interestingly, activation of AMPK by AICAR prevented the deleterious effect of palmitate on insulin signaling in N44 neurons (45).…”

Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells

“…Figure 2b shows that reduction of lon protease expression did not induce ER stress. In contrast, treatment with cholesterol and palmitate, known inducers of ER stress, did trigger ER stress [18,19] (Fig. 2b).…”