BcL10, a caspase recruitment domain (CARD)-containing protein identified
from the t(1;14)(p22;q32) breakpoint in mucosa-associated lymphoid tissue (MALT) lymphomas, has been shown to induce apoptosis and activate NF-kappaB in vitro. We show that one-third
of bcl10-/- embryos developed exencephaly, leading to embryonic lethality. Surprisingly, bcl10-/- cells retained susceptibility to various apoptotic stimuli in vivo and in vitro. However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes
are defective in antigen receptor or PMA/Ionomycin-induced activation. Early tyrosine phosphorylation, MAPK and AP-1 activation, and Ca2+ signaling were normal in mutant lymphocytes, but antigen receptor-induced NF-kappaB activation was absent. Thus, Bcl10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NF-kappaB activation.
And of course cell proliferation promotes growth of carcinoma cells.
Bcl10 Links Saturated Fat Overnutrition with Hepatocellular NF-κB Activation and Insulin Resistance
publisher's final edited version of this article is available free at Cell Rep
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Excess serum free fatty acids (FFAs) are fundamental to the pathogenesis of insulin resistance. With high fat feeding, FFAs activate NF-κB in target tissues, initiating negative cross-talk with insulin signaling. However,
the mechanisms underlying FFA-dependent NF-κB activation remain unclear. Here we demonstrate that the saturated FA, palmitate, requires Bcl10 for NF-κB activation in hepatocytes. Uptake of palmitate, metabolism to diacylglycerol, and subsequent
activation of PKC appear to mechanistically link palmitate with Bcl10, known as a central component of a signaling complex that, along with CARMA3 and MALT1, activates NF-κB downstream of selected cell surface receptors. Consequently, Bcl10-deficient
mice are protected from hepatic NF-κB activation and insulin resistance following brief high fat diet, suggesting that Bcl10 plays a major role in the metabolic consequences of acute overnutrition. Surprisingly, while CARMA3 also participates in the
palmitate response, MALT1 is completely dispensable, thereby revealing an apparent non-classical role for Bcl10 in NF-κB signaling.
Nutr. 2009 Sep; 4(3): 215–222.
Published online 2009 Aug 26. doi: 10.1007/s12263-009-0133-6
Diet-induced obesity increases NF-kB signaling in reporter mice
author1 Fred Haugen,1 Susanne Zadelaar,2 Robert Kleemann,2 Teake Kooistra,2 Christian A. Drevon,1 and Rune Blomhoff1
The nuclear factor (NF)-kB is a primary regulator of inflammatory responses and may
be linked to pathology associated with obesity. We investigated the progression of NF-kB activity during a 12-week feeding period on a high-fat diet (HFD) or a low-fat diet (LFD) using NF-?B luciferase reporter mice. In vivo imaging of luciferase
activity showed that NF-kB activity was higher in the HFD mice compared with LFD-fed mice. Thorax region of HFD females displayed fourfold higher activity compared with LFD females, while no such increase was evident in males. In male HFD mice, abdominal NF-kB
activity was increased twofold compared with the LFD males, while females had unchanged NF-kB activity in the abdomen by HFD. HFD males, but not females, exhibited evident glucose intolerance during the study.
In conclusion, HFD increased
NF-kB activity in both female and male mice. However, HFD differentially increased activity in males and females. The moderate increase in abdomen of male mice may be linked to glucose intolerance.
2015;64:2015–2027 | DOI: 10.2337/db14-0093
Central Inhibition of IKKb/NF-kB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance
Benzler,1 Goutham K. Ganjam,2 Dominik Pretz,1 Rebecca Oelkrug,1 Christiane E. Koch,1 Karen Legler,1 Sigrid Stöhr,1 Carsten Culmsee,2 Lynda M. Williams,3 and Alexander Tups1,4
Metabolic inflammation in the central
nervous system might be causative for the development of over nutrition induced metabolic syndrome and related disorders, such as obesity, leptin and insulin resistance, and type 2 diabetes. Here we investigated whether nutritive and genetic inhibition of
the central IkB kinase b (IKKb)/nuclear factor-kB (NF-kB) pathway in diet-induced obese (DIO) and leptin-deficient mice improves these metabolic impairments. A known prominent inhibitor of IKKb/NF-kB signaling is the dietary flavonoid butein. We initially
determined that oral, intraperitoneal, and intracerebroventricular administration of this flavonoid improved glucose tolerance and hypothalamic insulin signaling. The dosedependent glucose-lowering capacity was profound regardless of whether obesity was caused
by leptin deficiency or high-fat diet (HFD). To confirm the apparent
central role of IKKb/NF-kB signaling in the control of glucose and energy homeostasis, we genetically inhibited this pathway in neurons of the arcuate nucleus, one key center for
control of energy homeostasis, via specific adeno-associated virus serotype 2–mediated overexpression of IkBa, which inhibits NF-kB nuclear translocation. This treatment attenuated HFD-induced body weight gain, body fat mass accumulation, increased energy
expenditure, and reduced arcuate suppressor of cytokine signaling 3 expression, indicative for enhanced leptin signaling. These results reinforce a specific role of central proinflammatory IKKb/NF-kB signaling in the development and potential treatment of