Minireview: Inflammation and Obesity Pathogenesis: The Hypothalamus Heats Up

Thaler, Joshua P.; Schwartz, Michael W.

doi:10.1210/en.2010-0336

Cited by 265 publications

(218 citation statements)

References 57 publications

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“…Suppression in the anterior insula activity on satiation suggests its role in feeding behaviour in addition to its taste sensory processing (22,25,(74)(75)(76) . The hypothalamus is widely recognised as the gatekeeper to control food intake, highly influenced by nutrients, with evidence that hypothalamic dysfunction may lead to obesity (77) . Prior studies have shown the hypothalamus is modulated by satiety (76,78) ; however this modulation is inconsistent across BOLD studies, and may be due to its small structure, variability in position and close proximity to the sinus cavity.…”

Section: Effect Of Hunger and Satiety On Functional Mri Responsementioning

confidence: 99%

Imaging methodologies and applications for nutrition research: what can functional MRI offer?

Francis

Eldeghaidy

2014

Proc. Nutr. Soc.

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Food intake is influenced by a complex regulatory system involving the integration of a wide variety of sensory inputs across multiple brain areas. Over the past decade, advances in neuroimaging using functional MRI (f MRI) have provided valuable insight into these pathways in the human brain. This review provides an outline of the methodology of f MRI, introducing the widely used blood oxygenation level-dependent contrast for f MRI and direct measures of cerebral blood flow using arterial spin labelling. A review of f MRI studies of the brain's response to taste, aroma and oral somatosensation, and how fat is sensed and mapped in the brain in relation to the pleasantness of food, and appetite control is given. The influence of phenotype on individual variability in cortical responses is addressed, and an overview of f MRI studies investigating hormonal influences (e.g. peptide YY, cholecystokinin and ghrelin) on appetiterelated brain processes provided. Finally, recent developments in MR technology at ultrahigh field (7 T) are introduced, highlighting the advances this can provide for f MRI studies to investigate the neural underpinnings in nutrition research. In conclusion, neuroimaging methods provide valuable insight into the mechanisms of flavour perception and appetite behaviour. Over the past decade, advances in neuroimaging techniques, particularly functional MRI (f MRI), have provided valuable insight into central food-related pathways in the human brain. This review outlines recent advances in f MRI to understand flavour perception and human appetitive behaviour. A brief overview of the method of f MRI and the blood oxygenation level-dependent (BOLD) contrast generally used in f MRI is provided, together with how more direct measures of cerebral blood flow (CBF) can be assessed. f MRI studies of the brain's response to taste, aroma and flavour perception are outlined. The question of how fat is sensed and mapped in the brain in relation to the pleasantness of food, appetite control and hormonal influences is addressed. The role of neuroimaging studies to assess eating behaviour in obesity will be outlined. Finally, recent developments in MR technology, and the advances they can provide for future f MRI studies to investigate the neural underpinnings in nutrition research will be described. Principles of functional MRIf MRI has revolutionised the research of functional brain mapping and is now the most widely used method for mapping brain activity. f MRI measures brain activity *Corresponding author: Dr S. Francis, email susan.francis@nottingham.ac.uk ‡ The original version of this article was published with incorrect conference details. A notice detailing this has been published and the error rectified in the online and print PDF and HTML copies.

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Section: Effect Of Hunger and Satiety On Functional Mri Responsementioning

confidence: 99%

Imaging methodologies and applications for nutrition research: what can functional MRI offer?

Francis

Eldeghaidy

2014

Proc. Nutr. Soc.

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“…Some studies have shown that obesity is associated with inflammation in the hypothalamus (10)(11)(12)(13)(14), the central regulator of whole-body energy and glucose homeostasis (3)(4)(5)(6)(7)(8)(9). It appears that saturated fatty acids may directly activate toll-like receptor 4 (37), which subsequently leads to activation of the downstream JNK and IKKb/NF-kB cascade (13,17,38). In particular, modulation of the IKKb/NF-kB pathway at the level of IKKb and the upstream adaptor regulatory protein MyD88 suggested that this cascade, once activated, induces diet-induced resistance to the adiposity signals leptin and insulin (14,16).…”

Section: Discussionmentioning

confidence: 99%

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

et al. 2015

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Metabolic inflammation in the central nervous system might be causative for the development of overnutritioninduced 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 DIO-induced comorbidities.

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“…Obesity is closely linked to several metabolic disorders including insulin resistance and type 2 diabetes (T2D) (1)(2)(3)(4)(5)(6). However, the mechanisms underlying obesity-associated insulin resistance are not fully understood.…”

mentioning

confidence: 99%

“…Recently, an emerging hypothesis suggests that the alteration of wholebody insulin sensitivity could have a starting point in the brain and precisely in the hypothalamus (7). Indeed, chronic high-fat feeding promotes hypothalamic resistance to leptin and insulin through an inflammatory-dependent mechanism leading to impaired energy homeostasis, obesity, and insulin resistance (4,7). Furthermore, compelling evidence indicates that changes in adipocyte-derived factors in obesity dramatically affect insulin sensitivity (4)(5)(6).…”

mentioning

confidence: 99%

“…Indeed, chronic high-fat feeding promotes hypothalamic resistance to leptin and insulin through an inflammatory-dependent mechanism leading to impaired energy homeostasis, obesity, and insulin resistance (4,7). Furthermore, compelling evidence indicates that changes in adipocyte-derived factors in obesity dramatically affect insulin sensitivity (4)(5)(6). Among these adipokines, resistin is described as a causal factor for obesity-induced insulin resistance and T2D.…”

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confidence: 99%

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Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

et al. 2016

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Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.

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Minireview: Inflammation and Obesity Pathogenesis: The Hypothalamus Heats Up

Cited by 265 publications

References 57 publications

Imaging methodologies and applications for nutrition research: what can functional MRI offer?

Imaging methodologies and applications for nutrition research: what can functional MRI offer?

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

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