Hypothalamic inflammation in obesity and metabolic disease (original) (raw)
Regulation of energy homeostasis depends on input to the hypothalamus from metabolic feedback signals such as insulin and leptin (36). Diet-induced obesity causes activation of cytokines and inflammatory pathways in the hypothalamus (37). In parallel to the early occurrence of inflammation, three days of HFD feeding is sufficient to significantly reduce hypothalamic insulin sensitivity in rodents (38). Importantly, these processes precede inflammatory events in peripheral tissues, such as the liver (39).
Several studies have shown that specific lipid species are linked with resistance to the main adipostatic hormones insulin and leptin in peripheral tissues (40–43). Fatty acids, especially long-chain saturated fatty acids (SFAs), can acutely modulate neuronal control of energy homeostasis. Enteric gavage with SFAs induces hypothalamic inflammation within days, whereas administration of monounsaturated fatty acids did not result in compromised hypothalamic function (44). SFAs, such as palmitate and stearate, are able to cross the blood-brain barrier (BBB) and accumulate specifically in the hypothalamus, where they blunt anorexigenic signaling by insulin and leptin and thereby promote positive energy balance (44–46). SFAs, unlike unsaturated fatty acids, trigger the activation of inflammatory signaling cascades via TLR4 signaling and the adaptor molecule myeloid differentiation primary response gene 88 (MyD88) (refs. 47, 48, and Figure 2). Pharmacologic inhibition of neuronal TLR4 signaling inhibits fatty acid–induced insulin (45) and leptin resistance (49). Furthermore, mice with CNS-specific ablation of MyD88 are protected from HFD-induced weight gain and deterioration of glucose metabolism (48). Downstream signaling occurs via the IKK complex and NF-κB activation, leading to the expression of proinflammatory genes in the hypothalamus (45, 49, 50). Brain-specific activation of IKKβ results in increased food intake and body weight gain and interrupts central insulin and leptin signaling (50). Furthermore, activation of NF-κB induces expression of suppressor of cytokine signaling 3 (SOCS3), which subsequently inhibits neuronal insulin signaling (50). Upon acute exposure to HFD, SOCS3 is upregulated in AgRP neurons, leading to hyperphagia, energy imbalance, and development of insulin and leptin resistance. In contrast, intracerebroventricular (ICV) injections of unsaturated fatty acids, namely omega-3 fatty acids, restore leptin and insulin sensitivity (51–53).
Molecular pathways of metabolic inflammation in the hypothalamus. Activation of the insulin signaling pathway leads to FOXO1 phosphorylation, resulting in nuclear exclusion and inhibition of FOXO1-mediated activation/repression of target genes. By removing FOXO1 repression, insulin increases the anorexigenic tone via induced POMC gene expression in POMC neurons with simultaneous suppressed AgRP/NPY expression in AgRP neurons. Binding of leptin to the leptin receptor activates and recruits STAT3. Tyrosine phosphorylation triggers dimerization of STAT3 and translocation to the nucleus, where the STAT3 complex induces POMC gene expression in POMC neurons and suppresses AgRP/NPY in AgRP neurons. TNF-α binding promotes the trimerization of the TNF receptor, which promotes the assembly of a signaling complex that activates JNK and inhibits cellular insulin signaling. In addition, TNF signaling triggers activation of NF-κB. In the TLR4 signaling pathway, MyD88 serves as a scaffold protein for downstream signaling molecules. NF-κB dimers are sequestered in the cytoplasm by the inhibitor of NF-κB α (IκBα). Phosphorylation by the IKK complex and subsequent proteolysis of IκBα leads to the release and nuclear translocations of NF-κB. NF-κB heterodimer RelA and p50 bind to motifs in the promoter of targets genes, such as SOCS3, a common inhibitor of insulin and leptin signaling, and proinflammatory genes. Induction of ceramides leads to increased phosphorylation and localization of PKC with caveolin-enriched lipid microdomains to inactivate Akt.
TLR4-mediated signaling pathways also activate the MAPK pathway, which triggers p38- and JNK-dependent signaling and activation of various activator protein-1 (AP-1) subunits. JNK mediates inhibitory phosphorylation of insulin receptor substrate (IRS) proteins at serine 307, thereby impairing insulin action (54). Constitutive JNK activation in AgRP neurons of the hypothalamus induces weight gain and adiposity in mice as a consequence of hyperphagia (55). In fact, conditional JNK1 knockout specifically in the brain, but not in other tissues, leads to protection against insulin resistance, hyperinsulinemia, and glucose intolerance (56, 57). Interestingly, activation of TLR4 signaling controls apoptotic activity of cells in the hypothalamus but subsequently activates proinflammatory pathways that ultimately lead to the development of central insulin and leptin resistance (58).
Elevations of sphingolipids such as ceramides, whose synthesis depends on SFAs, and alterations in downstream sphingolipid-mediated signaling pathways might provide an additional mechanism by which SFA-induced inflammatory pathways mediate the deterioration of insulin and leptin signaling (59, 60). Induction of ceramides during obesity has been shown to promote insulin resistance (61). Ceramide is a common mediator of cellular stress, and inhibition of ceramide biosynthesis blocks the ability of SFAs to induce insulin resistance in obese rodent models (62). Although hypothalamic metabolic inflammation affects both males and females, sphingolipids and palmitic acid show a sexually dimorphic accumulation pattern during high-fat feeding and increase more in the CNS of male mice than in female mice (63). Furthermore, SFAs are able to mediate central insulin resistance via activation of the PKC isoform PKC-θ. Palmitic acid induces translocation of PKC-θ to the cell membrane exclusively in AgRP neurons, resulting in inhibition of PI3K signaling (64). This finding is specific for palmitic acid, as CNS exposure to the monounsaturated fatty acid oleic acid did not induce insulin resistance. Conversely, ARC-specific knockdown of PKC-θ attenuated diet-induced obesity (64). These HFD-induced perturbations are further amplified by the ER system via activation of unfolded protein response (UPR) signaling pathways (52, 65, 66). In the hypothalamus, ER stress and activation of UPR signaling pathways lead to the development of insulin and leptin resistance. ER stress and IKK/NF-κB promote each other during HFD feeding and accelerate the energy imbalance underlying obesity (50). Central administration of an ER stress inducer inhibits the anorexigenic and weight-reducing effects of leptin and insulin (67). Conversely, mice with neuron-specific deletion of ER stress activator X-box binding protein 1 (Xbp1) exhibit increased leptin resistance and adiposity (65). Hypothalamic POMC neurons are critical mediators of hypothalamic ER stress. Constitutive expression of Xbp1s selectively in POMC neurons represses Socs3 and protein tyrosine phosphatase 1B (Ptp1B) expression and protects against HFD-induced obesity (68). ER stress and the UPR are potent regulators of POMC neurons and are therefore interesting targets for the amelioration of central insulin and leptin resistance and the regulation of metabolic disorders.
Collectively, multiple inflammatory and stress response pathways are rapidly activated during HFD-feeding and promote the development of neuronal insulin and leptin resistance, raising the possibility that nutrient excess itself is the primary driver of hypothalamic inflammation.