Over the last years, hypothalamic inflammation has been linked to the development and progression of obesity and its sequelae. There is accumulating evidence that this inflammation not only impairs ...energy balance but also contributes to obesity-associated insulin resistance. Elevated activation of key inflammatory mediators such as JNK and IκB kinase (IKK) occurs rapidly upon consumption of a high-fat diet, even prior to significant weight gain. This activation of hypothalamic inflammatory pathways results in the uncoupling of caloric intake and energy expenditure, fostering overeating and further weight gain. In addition, these inflammatory processes contribute to obesity-associated insulin resistance and deterioration of glucose metabolism via altered neurocircuit functions. An understanding of the contributions of different neuronal and non-neuronal cell types to hypothalamic inflammatory processes, and delineation of the differences and similarities between acute and chronic activation of these inflammatory pathways, will be critical for the development of novel therapeutic strategies for the treatment of obesity and metabolic syndrome.
The 'obesity epidemic' represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic ...comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed.
The central nervous system (CNS) receives information from afferent neurons, circulating hormones, and absorbed nutrients and integrates this information to orchestrate the actions of the ...neuroendocrine and autonomic nervous systems in maintaining systemic metabolic homeostasis. Particularly the arcuate nucleus of the hypothalamus (ARC) is of pivotal importance for primary sensing of adiposity signals, such as leptin and insulin, and circulating nutrients, such as glucose. Importantly, energy state-sensing neurons in the ARC not only regulate feeding but at the same time control multiple physiological functions, such as glucose homeostasis, blood pressure, and innate immune responses. These findings have defined them as master regulators, which adapt integrative physiology to the energy state of the organism. The disruption of this fine-tuned control leads to an imbalance between energy intake and expenditure as well as deregulation of peripheral metabolism. Improving our understanding of the cellular, molecular, and functional basis of this regulatory principle in the CNS could set the stage for developing novel therapeutic strategies for the treatment of obesity and metabolic syndrome. In this review, we summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.
The central nervous system (CNS) has an important role in the regulation of peripheral insulin sensitivity and glucose homeostasis. Research in this dynamically developing field has progressed ...rapidly due to techniques allowing targeted transgenesis and neurocircuitry mapping, which have defined the primary responsive neurons, associated molecular mechanisms and downstream neurocircuitries and processes involved. Here we review the brain regions, neurons and molecular mechanisms by which the CNS controls peripheral glucose metabolism, particularly via regulation of liver, brown adipose tissue and pancreatic function, and highlight the potential implications of these regulatory pathways in type 2 diabetes and obesity.
The brain controls peripheral glucose metabolism, for example by modulating hepatic gluconeogenesis or by regulating glucose uptake into brown adipose tissue. Here, the authors review the brain regions, neurons and molecular mechanisms involved in these processes, and discuss their relevance to disease.
Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk ...rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain ...barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGFΔmyel mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGFΔmyel mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer’s disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity.
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•Acute high-fat feeding suppresses GLUT1 expression at the blood-brain barrier (BBB)•Macrophages at the BBB increase VEGF expression upon prolonged HFD feeding•Inducible GLUT1 deletion in brain endothelial cells leads to increased VEGF secretion•Myeloid-cell-specific disruption of VEGF impairs cognitive function in obesity
Acute high-fat feeding suppresses brain glucose uptake. To preserve cognitive function after prolonged feeding on a high-fat diet and to forestall neurodegeneration in obesity, there is a compensatory upregulation of glucose transporters at the blood-brain barrier as a result of inflammatory signals from perivascular macrophages.
Highlights • IL-6 has varied roles and its effects are highly context- and tissue-dependent. • IL-6 is largely beneficial for tissue homeostasis, with roles in resolving inflammation. • IL-6 has ...detrimental effects during carcinogenesis and in chronic inflammation.
Maternal metabolic homeostasis exerts long-term effects on the offspring’s health outcomes. Here, we demonstrate that maternal high-fat diet (HFD) feeding during lactation predisposes the offspring ...for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) neurons, electrophysiological properties of POMC neurons, and posttranslational processing of POMC remain unaffected in response to maternal HFD feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation, and impaired glucose-stimulated insulin secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections, and show that abnormal insulin signaling contributes to this effect.
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•Maternal HFD feeding during lactation impairs metabolic health of the offspring•Maternal HFD during lactation impairs formation of melanocortin projections•Abnormal insulin action in POMC neurons impairs POMC projections to preautonomic PVH•Abrogating POMC insulin action improves glucose metabolism despite maternal HFD
Mouse mothers that eat a high-fat diet during lactation have offspring predisposed to obesity and diabetes due to the impaired establishment of hypothalamic neurocircuits that regulate metabolism.
Ceramide accumulation is a hallmark in the manifestation of numerous obesity-related diseases, such as type 2 diabetes mellitus and atherosclerosis. Until the early 2000s, ceramides were viewed as a ...homogenous class of sphingolipids. However, it has now become clear that ceramides exert fundamentally different effects depending on the specific fatty acyl chain lengths, which are integrated into ceramides by a group of enzymes known as dihydroceramide synthases. In addition, alterations in ceramide synthesis, trafficking and metabolism in specific cellular compartments exert distinct consequences on metabolic homeostasis. Here, we examine the emerging concept of how the intracellular localization of ceramides with distinct acyl chain lengths can regulate glucose metabolism, thus emphasizing their potential as targets in the development of novel and specific therapies for obesity and obesity-associated diseases.
Obesity represents a major risk factor for the development of insulin and leptin resistance, ultimately leading to a pleiotropic spectrum of metabolic alterations. However, resistance to both ...hormones does not uniformly affect all target cells and intracellular signaling pathways. In contrast, numerous clinical phenotypes arise from selective hormone resistance, leading to inhibition of defined intracellular signaling pathways in some tissues, while in other cell types hormone action is maintained or even overactivated. Here, we review the molecular mechanisms and clinical outcomes resulting from selective insulin and leptin resistance, which should ultimately guide future strategies for the treatment of obesity-associated diseases.
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