Septic shock results from bacterial infection and is associated with multi-organ failure, high mortality, and cardiac dysfunction. Sepsis causes both myocardial inflammation and energy depletion. We hypothesized that reduced cardiac energy production is a primary cause of ventricular dysfunction in sepsis. The JNK pathway is activated in sepsis and has also been implicated in impaired fatty acid oxidation in several tissues. Therefore, we tested whether JNK activation inhibits cardiac fatty acid oxidation and whether blocking JNK would restore fatty acid oxidation during LPS treatment. LPS treatment of C57BL/6 mice and adenovirus-mediated activation of the JNK pathway in cardiomyocytes inhibited peroxisome proliferator-activated receptor ␣ expression and fatty acid oxidation. Surprisingly, none of the adaptive responses that have been described in other types of heart failure, such as increased glucose utilization, reduced ␣MHC:␤MHC ratio or induction of certain microRNAs, occurred in LPS-treated mice. Treatment of C57BL/6 mice with a general JNK inhibitor (SP600125) increased fatty acid oxidation in mice and a cardiomyocyte-derived cell line. JNK inhibition also prevented LPS-mediated reduction in fatty acid oxidation and cardiac dysfunction. Inflammation was not alleviated in LPS-treated mice that received the JNK inhibitor. We conclude that activation of JNK signaling reduces fatty acid oxidation and prevents the peroxisome proliferator-activated receptor ␣ downregulation that occurs with LPS.Septic shock is the most severe complication of sepsis and is associated with reduced cardiac contractility (1, 2). Hearts rely mostly (70%) on fatty acid (FA) 3 oxidation for energy homeostasis (3), and in sepsis, cardiac FA oxidation is markedly reduced. Unlike heart failure (4), this reduction of FA oxidation in sepsis is not compensated by a simultaneous increase in glucose oxidation (5-7). Thus, sepsis leads to cardiac energy deficiency.LPS is a bacterial cell wall component that induces many of the pathophysiological consequences of sepsis, including cardiac dysfunction. LPS associates with plasma LPS-binding protein and targets cluster of differentiation (CD)14 and toll-like receptor 4 (8). This binding leads to production of inflammatory cytokines, such as TNF␣, IL-1, and IL-6, which might directly alter heart function (9 -12). LPS also alters cardiac energy utilization by reducing the expression of peroxisome proliferator-activated receptor (PPAR)␣ and its downstream genes required for FA oxidation (13,14). It is unknown whether the LPS-induced reduction in cardiac energy production is mediated by inflammation.LPS activates the JNK signaling pathway (15,16). JNK is a stress-activated protein kinase (17) that phosphorylates c-Jun, which then forms homo-or heterodimers with c-Fos or activating transcription factor, forming the activating protein 1 complex (18). LPS activates JNK in the heart, but it is not clear whether this pathway leads to impaired cardiac FA oxidation. Inhibition of JNK improves FA oxidation in...

Both obesity and diabetes mellitus are associated with alterations in lipid metabolism as well as a change in bone homeostasis and osteoclastogenesis. We hypothesized that increased fatty acid levels affect bone health by altering precursor cell differentiation and osteoclast activation. Here we show that palmitic acid (PA, 16:0) enhances receptor activator of NF-κB ligand (RANKL)-stimulated osteoclastogenesis and is sufficient to induce osteoclast differentiation even in the absence of RANKL. TNFα expression is crucial for PA-induced osteoclastogenesis, as shown by increased TNFα mRNA levels in PA-treated cells and abrogation of PA-stimulated osteoclastogenesis by TNFα neutralizing antibodies. In contrast, oleic acid (OA, 18:1) does not enhance osteoclast differentiation, leads to increased intracellular triglyceride accumulation, and inhibits PA-induced osteoclastogenesis. Adenovirus-mediated expression of diacylglycerol acyl transferase 1 (DGAT1), a gene involved in triglyceride synthesis, also inhibits PA-induced osteoclastogenesis, suggesting a protective role of DGAT1 for bone health. Accordingly, Dgat1 knockout mice have larger bone marrow-derived osteoclasts and decreased bone mass indices. In line with these findings, mice on a high-fat PA-enriched diet have a greater reduction in bone mass and structure than mice on a high-fat OA-enriched diet. Thus, we propose that TNFα mediates saturated fatty acid-induced osteoclastogenesis that can be prevented by DGAT activation or supplementation with OA.

We used human cardiomyocyte-derived cells to create an in vitro model to study lipid metabolism and explored the effects of PPARγ, ACSL1 and ATGL on fatty acid-induced ER stress. Compared to oleate, palmitate treatment resulted in less intracellular accumulation of lipid droplets and more ER stress, as measured by upregulation of CHOP, ATF6 and GRP78 gene expression and phosphorylation of eukaryotic initiation factor 2a (EIF2a). Both ACSL1 and PPARγ adenovirus-mediated expression augmented neutral lipid accumulation and reduced palmitate-induced upregulation of ER stress markers to levels similar to those in the oleate and control treatment groups. This suggests that increased channeling of non-esterified free fatty acids (NEFA) towards storage in the form of neutral lipids in lipid droplets protects against palmitate-induced ER stress. Overexpression of ATGL in cells incubated with oleate-containing medium increased NEFA release and stimulated expression of ER stress markers. Thus, inefficient creation of lipid droplets as well greater release of stored lipids induces ER stress.