Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
Xiaoqing Zhang1, 4, Guo Zhang1, 4, Hai Zhang1, 2, 4, Michael Karin3, Hua Bai1 and Dongsheng Cai1, 
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Introduction
The hypothalamus is the “headquarters” for regulating energy homeostasis ([Elmquist and Flier, 2004] and [Schwartz and Porte, 2005]). This regulation is primarily mediated in the mediobasal hypothalamus (MBH) by orexigenic AGRP neurons that coexpress two neuropeptides—NPY (neuropeptide Y) and AGRP (agouti-related protein)—and anorexigenic POMC neurons that coexpress two other neuropeptides—CART (cocaine- and amphetamine-regulated transcript) and POMC (proopiomelanocortin). Leptin and insulin work in these neurons to control these neuropeptides, leading to normal energy balance and the prevention of obesity. Research has revealed that insulin signaling and leptin signaling in the hypothalamus are integrated through at least PI-3K ([Morton et al., 2005] and [Xu et al., 2005]), FoxO1 ([Kim et al., 2006] and [Kitamura et al., 2006]), and mTOR (Cota et al., 2006). Recent studies have also identified two common inhibitors for insulin and leptin signaling, SOCS3 (Howard and Flier, 2006) and PTP1B (Bence et al., 2006), but their significance in causing disease is poorly understood.Loss of leptin or insulin signaling in the hypothalamus is sufficient to induce or promote obesity and type 2 diabetes (T2D), as clearly demonstrated in various genetic mouse models with neuronal ablation of insulin signaling ([Bruning et al., 2000], [Burks et al., 2000] and [Obici et al., 2002]) or leptin signaling ([Balthasar et al., 2004], [Bates et al., 2003] and [Lee et al., 1996]). In obesity and T2D, along with striking hyperinsulinemia and hyperleptinemia, insulin and leptin levels in the cerebrospinal fluid are elevated, all of which indicate a chronic state of central insulin and leptin resistance. Central administration of insulin or leptin consistently compromises the ability to control food intake in animals during the development of dietary obesity, confirming that hypothalamic (or central) leptin and insulin resistance contribute to the pathophysiology of obesity and T2D. Recent research has also dissociated overnutrition from obesity, demonstrating that overnutrition directly blunts central insulin and leptin sensitivity before the onset of obesity ([Wang et al., 2001] and [Woods et al., 2004]). However, how central insulin and leptin resistance are induced by overnutrition and whether core mechanism(s) might be involved are both currently unknown.
IKKβ/NF-κB is a master switch and central regulator of innate immunity and related functions (Hayden and Ghosh, 2008). In the quiescent state, NF-κB remains inactive in the cytoplasm through binding to the inhibitory protein IκB. Activation of IKKβ by phosphorylation at S177 and S181 induces phosphorylation of its substrate IκBα at S32 and S36, ubiqitination, and subsequent proteosomal degradation. The disappearance of IκBα releases NF-κB to translocate into the nucleus where it mediates the transcription of its target genes. Research during recent decades recognized that overnutrition can induce inflammatory responses in the peripheral metabolic tissues (metabolic inflammation) and therefore cause various metabolic defects in those tissues that underlie T2D ([Hotamisligil, 2006] and [Lehrke and Lazar, 2004]). In this context, IKKβ was identified as a target for an anti-inflammatory therapy that was effective for obesity-associated T2D (Yuan et al., 2001). Subsequently, a series of discoveries revealed that IKKβ/NF-κB located in peripheral metabolic tissues affects glucose and protein metabolism in tissue-specific manners ([Arkan et al., 2005], [Cai et al., 2004] and [Cai et al., 2005]). However, it still remains unexplored whether metabolic inflammation and related mediators could target the metabolic regulatory pathways in the central nervous system (CNS), thus leading to a family of diseases related to overnutrition and obesity. In this study, we explored whether IKKβ/NF-κB is the fundamental connection between overnutrition and the dysfunctions of hypothalamic signaling that cause obesity and associated problems.
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Discussion
Overnutrition Subverts the Innate Immune Response of Hypothalamic IKKβ/NF-κB
Obesity and its co-morbidities represent one of the greatest epidemic and public health problems facing our society. Relatively recent environmental changes, especially overnutrition, are clearly responsible for the high prevalence of these diseases. Faced with the energy abundance typical of today's developed world, our control systems have yet to evolve to readily regulate the body's energy balance. This newly emerged challenge to the control systems in our bodies has led to excessive energy stores (fat) and ultimately to disease. While the CNS control systems, like the hypothalamus, might conceivably be essential for this regulatory failure, the participating molecular program(s) remain unknown.
Our work shows that the “master switch” innate immunity regulator, IKKβ/NF-κB, while highly enriched in the hypothalamic neurons is normally not activated. Importantly, this pathway can be activated in the hypothalamic neurons by the chronic overnutrition that causes obesity. Such activation can even be mimicked without obesity by an acute but extreme oversupply of various nutrients to the CNS. Our findings indicate that persistent signals to the CNS under conditions of overnutrition can atypically stimulate an innate immunity-like response directed by IKKβ/NF-κB in the hypothalamic neurons; this process affects the neuronal regulation of energy balance (Figure 7). Overall, our findings align with the emerging view that evolution integrated some regulatory pathways that govern the body's reactions to both pathogens and nutrition (Hotamisligil, 2006). We postulate that the hypothalamus might have developed the unique property of responding to extreme environmental stimuli (previously pathogens, now overnutrition) by using IKKβ/NF-κB to affect vital systems. Thus, although the near-instantaneous signaling of hypothalamic IKKβ/NF-κB might once have been critical for survival in a pathogen-filled environment by helping innate immunity (an energy-intensive process), this signaling—as our study demonstrates—might now be very responsive and truly detrimental in today's near-constant calorie-rich environment. Hypothalamic IKKβ/NF-κB could underlie the entire family of modern diseases induced by overnutrition and obesity.
....Hypothalamic IKKβ as a Potential Target to Counter Obesity and T2D
Our work also marks an initial attempt to study whether inhibiting an innate immune pathway in the hypothalamus could help to calibrate the set point of nutritional balance and therefore aid in counteracting energy imbalance and diseases induced by overnutrition. These results reveal that dietary obesity can be largely prevented by inhibiting IKKβ/NF-κB either virally or genetically, whether broadly throughout the CNS, locally in the related hypothalamic regions, or precisely in a defined subpopulation of hypothalamic neurons. Altogether, our results suggest a novel therapeutic strategy for combating the ever-increasing spread of obesity and associated diseases. We recognize that the significance of this strategy has yet to be realized in clinical practice; currently, most anti-inflammatory therapies have limited direct effects on IKKβ/NF-κB and limited capacity to be concentrated in the CNS. Nonetheless, our discoveries offer potential for treating these serious diseases. Because we also revealed that IKKβ/NF-κB normally remains inactive in the CNS, suppressing IKKβ/NF-κB in the hypothalamus is likely a safe approach. However, challenges still remain, such as finding methods to selectively suppress this pathway in the CNS, that will certainly inspire future research.
Cell Vol 135, Issue 1, 3 October 2008, Pages 61-73
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