Obesity promotes the development of numerous cancers, such as liver and colorectal cancers, which is at least partly due to obesity-induced, chronic, low-grade inflammation. In particular, the ...recruitment and activation of immune cell subsets in the white adipose tissue systemically increase proinflammatory cytokines, such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). These proinflammatory cytokines not only impair insulin action in metabolic tissues, but also favor cancer development. Here, we review the current state of knowledge on how obesity affects inflammatory TNFα and IL-6 signaling in hepatocellular carcinoma and colorectal cancers.
Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1–6). It remains ...unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6Δ/Δ) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition.
Display omitted
•CERS6 expression in human WAT correlates with adiposity and insulin resistance•CerS6-deficient mice are protected from DIO and glucose intolerance•Both BAT- and liver-specific CerS6 deletion improves glucose tolerance•CerS6 inhibition provides a specific approach to treat glucose intolerance
Turpin et al. link alterations in the C16:0 ceramide-generating enzyme, CerS6, with obesity and diabetes in humans and mice and characterize the beneficial metabolic effects associated with loss of function in mice. Therapeutic CerS6 inhibition could circumvent the side effects of global ceramide synthesis inhibition.
The steadily increasing obesity epidemic affects currently 30% of western populations and is causative for numerous disorders. It has been demonstrated that immune cells such as macrophages reside in ...or infiltrate metabolic organs under obese conditions and cause the so-called low-grade inflammation or metaflammation that impairs insulin action thus leading to the development of insulin resistance. Here, we report on data that specifically address macrophage biology/physiology in obesity-induced inflammation and insulin resistance.
Effector CD4
+ T cell subsets, whose differentiation is facilitated by distinct cytokine cues, amplify the corresponding type of inflammatory response. Regulatory T (Treg) cells integrate ...environmental cues to suppress particular types of inflammation. In this regard, STAT3, a transcription factor essential for T helper 17 (Th17) cell differentiation, is necessary for Treg cell-mediated control of Th17 cell responses. Here, we showed that anti-inflammatory interleukin-10 (IL-10), and not proinflammatory IL-6 and IL-23 cytokine signaling, endowed Treg cells with the ability to suppress pathogenic Th17 cell responses. Ablation of the IL-10 receptor in Treg cells resulted in selective dysregulation of Th17 cell responses and colitis similar to that observed in mice harboring STAT3-deficient Treg cells. Thus, Treg cells limit Th17 cell inflammation by serving as principal amplifiers of negative regulatory circuits operating in immune effector cells.
► IL-10 induces robust Stat3 activation in Treg cells as compared to naive T cells ► Ablation of IL-10R on Treg cells results in dysregulated Th17 cell responses ► IL-10R signaling facilitates IL-10 production by Treg cells ► Treg cells serve as amplifiers of existing negative regulation from effector cells
Colorectal cancer (CRC) is one of the most lethal cancers worldwide in which the vast majority of cases exhibit little genetic risk but are associated with a sedentary lifestyle and obesity. Although ...the mechanisms underlying CRC and colitis-associated colorectal cancer (CAC) remain unclear, we hypothesised that obesity-induced inflammation predisposes to CAC development. Here, we show that diet-induced obesity accelerates chemically-induced CAC in mice via increased inflammation and immune cell recruitment. Obesity-induced interleukin-6 (IL-6) shifts macrophage polarisation towards tumour-promoting macrophages that produce the chemokine CC-chemokine-ligand-20 (CCL-20) in the CAC microenvironment. CCL-20 promotes CAC progression by recruiting CC-chemokine-receptor-6 (CCR-6)-expressing B cells and γδ T cells via chemotaxis. Compromised cell recruitment as well as inhibition of B and γδ T cells protects against CAC progression. Collectively, our data reveal a function for IL-6 in the CAC microenvironment via lymphocyte recruitment through the CCL-20/CCR-6 axis, thereby implicating a potential therapeutic intervention for human patients.
Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, ...whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.
Display omitted
•Central IL-6 action suppresses feeding and improves glucose tolerance•IL-6-mediated metabolic actions via the CNS are enhanced in obesity•Beneficial central IL-6 effects on metabolism are exerted via IL-6 trans-signaling•Blocking of IL-6 trans-signaling in the PVH attenuates its beneficial metabolic effects
Timper et al. find that central IL-6 improves energy and glucose homeostasis via IL-6 trans-signaling. IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.
Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and ...leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
Display omitted
•Inflammatory signaling in AgRP neurons promotes obesity and insulin resistance•JNK and IKK activations in AgRP neurons have distinct metabolic consequences•JNK activation in AgRP neurons causes cellular and systemic leptin resistance•IKK activation in AgRP neurons leads to cellular and systemic insulin resistance
Inflammatory signaling in the CNS is crucial in the development of obesity-associated insulin and leptin resistance. Tsaousidou et al. demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons is sufficient to induce weight gain and leptin resistance in mice, whereas IKK2 activation fails to cause obesity but blunts insulin signaling and impairs systemic glucose homeostasis. The data reveal distinct effects of c-Jun N-terminal kinase (JNK)- and inhibitor of nuclear factor kappa-B kinase (IKK)-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations ...to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.
Display omitted
•Intersectional mapping of sensory neurons identifies distinct gut innervation patterns•Gut-innervating GLP1R+ vagal afferents relay anorexigenic signals to brainstem neurons•Gut-innervating GPR65+ vagal afferent stimulation increases hepatic glucose production•GLP1R+ vagal afferent activity is required to control glycemia during feeding
Borgmann et al. devise an intersectional genetic approach to probe the contribution of molecularly defined sensory neurons in gut-brain communication. They identify that distinct gut-innervating vagal afferents differentially control food intake and peripheral glucose metabolism, and engage distinct downstream circuits in the brain.
Aging is a progressive decline of body function, during which many tissues accumulate few cells with high levels of deleted mitochondrial DNA (mtDNA), leading to a defect of mitochondrial functions. ...Whether this mosaic mitochondrial deficiency contributes to organ dysfunction is unknown. To investigate this, we generated mice with an accelerated accumulation of mtDNA deletions in the myocardium, by expressing a dominant-negative mutant mitochondrial helicase. These animals accumulated few randomly distributed cardiomyocytes with compromised mitochondrial function, which led to spontaneous ventricular premature contractions and AV blocks at 18 months. These symptoms were not caused by a general mitochondrial dysfunction in the entire myocardium, and were not observed in mice at 12 months with significantly lower numbers of dysfunctional cells. Therefore, our results suggest that the disposition to arrhythmia typically found in the aged human heart might be due to the random accumulation of mtDNA deletions and the subsequent mosaic respiratory chain deficiency.
Display omitted
•Cardiomyocytes steadily accumulate mitochondrial DNA deletions with aging•This leads to the development of a tissue mosaic of mitochondrial deficiency•Impaired mitochondrial function in few cells promotes cardiac arrhythmia
Baris et al. test the idea of mosaic respiratory chain deficiency contributing to aging-related human cardiac disease. Using a genetic mouse model of accelerated accumulation of mtDNA deletions in the heart, they show that a few cardiomyocytes with mitochondrial DNA deletions progressively accumulate during aging, leading to cardiac arrhythmias.
Low-grade inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Interleukin-6 (IL-6) is a crucial regulator of T cells and is increased in ...obesity. Here we report that classical IL-6 signalling in T cells promotes inflammation and insulin resistance during the first 8 weeks on a high-fat diet (HFD), but becomes dispensable at later stages (after 16 weeks). Mice with T cell-specific deficiency of IL-6 receptor-α (IL-6Rα
) exposed to a HFD display improved glucose tolerance, insulin sensitivity and inflammation in liver and EWAT after 8 weeks. However, after 16 weeks, insulin resistance in IL-6Rα
epididymal white adipose tissue (EWAT) is comparable to that of controls, whereas the inflammatory profile is significantly worse. This coincided with a shift from classical T cell IL-6 signalling at 8 weeks, to enhanced IL-6 trans-signalling at 16 weeks. Collectively, our studies reveal that IL-6 action in T cells through classical IL-6 signalling promotes inflammation and insulin resistance early during obesity development, which can be compensated for by enhanced IL-6 trans-signalling at later stages.
PDF
