Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

Abstract

X. (2015). Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice. Journal of Nutritional Biochemistry, 26 (5), 541-548. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice AbstractThe consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6 J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling ( JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. Abstract:The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules, and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1), and a pro-inflammatory response (TNF-α, IL1-β, IL-6, and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei.Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2), ...

Lipid Processing in the Brain: A Key Regulator of Systemic Metabolism

“…Nonetheless, a number of recent studies highlight the role of central FAs in hepatic lipid homeostasis. For example, central administration of PA resulted in impaired leptin signaling and pro-inflammatory response in the MBH and PVN (88). Furthermore, this was coupled with blunted leptin-induced changes in hepatic gluconeogenesis, glucose transportation, and lipogenesis (88).…”

“…For example, central administration of PA resulted in impaired leptin signaling and pro-inflammatory response in the MBH and PVN (88). Furthermore, this was coupled with blunted leptin-induced changes in hepatic gluconeogenesis, glucose transportation, and lipogenesis (88). In a recent report, Yue and colleagues have shown that infusion of OA directly into the MBH activates a PKC-δ to K ATP channel axis, which suppresses VLDL-TG secretion in rats (89).…”

The central role of hypothalamic inflammation in the acute illness response and cachexia

“…Central administration of the saturated fat palmitic acid not only induces a program of hypothalamic inflammation, including increased local expression of cytokines IL-6, IL-1β, and TNFα, but it also leads to decreases in leptin-induced mRNA expression related to gluconeogenesis, glucose transport, and lipogenesis in the liver [49]. These peripheral pathological outcomes are abrogated by reduction of hypothalamic inflammation.…”

Extra virgin olive oil reduces liver oxidative stress and tissue depletion of long-chain polyunsaturated fatty acids produced by a high saturated fat diet in mice

“…Liver fat accumulation and oxidative stress would be linked to the reduction of the n-3 and n-6 LCPUFA observed in the liver, erythrocytes and the brain (Tables 4 to 6), effects that may be directly linked to the increase in systemic and hepatic oxidative stress parameters previously observed in the mice fed the HFD (Valenzuela et al, 2015). It has been described that the accumulation of fat in the liver (from over load of saturated fat and refined carbohydrates of nutritional origin) generates a decrease in the activity of the nuclear peroxisome proliferator-activated receptor transcription factor alpha (PPAR-α) as a direct consequence of the reduction in tissue levels of n-3 LCPUFA and, in addition, an increase in the activity of the sterol regulatory element binding protein transcription factor -1 c (SREBP-1 c) (Pawlak et al, 2015), thus promoting a pro-lipogenic state, particularly expressed as greater synthesis of 16:0, as shown in tables 4, 5 and 6, and a reduction in the oxidation of fatty acids as a source of energy (Cheng et al, 2015). The fall of the liver levels of n-3 LCPUFA, especially EPA and DHA, also severely affects the development of pro-oxidative and pro-inflammatory states as a result of the reduction in the erythroid nuclear transcriptionrelated factor 2 (Nrf-2) (Kwan et al, 2015) and a strengthening of a hepatic pro-inflammatory state because an increase in the activity of the nuclear transcription factor kappa-B (NF-κB) (Videla et al, 2009).…”