While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation.

Background: African malaria vectors bite predominantly indoors at night so sleeping under an Insecticide-Treated Net (ITN) can greatly reduce malaria risk. Behavioural adaptation by mosquitoes to increasing ITN coverage could allow vector mosquitoes to bite outside of peak sleeping hours and undermine efficacy of this key malaria prevention measure.

OBJECTIVEMacrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage recruitment to adipose tissue during states of energetic excess are not clear. Sirtuin 1 (SirT1) is an essential nutrient-sensing histone deacetylase, which is increased by caloric restriction and reduced by overfeeding. We discovered that SirT1 depletion causes anorexia by stimulating production of inflammatory factors in white adipose tissue and thus posit that decreases in SirT1 link overnutrition and adipose tissue inflammation.RESEARCH DESIGN AND METHODSWe used antisense oligonucleotides to reduce SirT1 to levels similar to those seen during overnutrition and studied SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout animals. Finally, we analyzed subcutaneous adipose tissue biopsies from two independent cohorts of human subjects.RESULTSWe found that inducible or genetic reduction of SirT1 in vivo causes macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation caused by chronic high-fat feeding. We also found that SirT1 expression in human subcutaneous fat is inversely related to adipose tissue macrophage infiltration.CONCLUSIONSReduction of adipose tissue SirT1 expression, which leads to histone hyperacetylation and ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition in rodents and humans. Our results suggest that SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress.

Caspase-1 is a cysteine protease that can be activated by both endogenous and exogenous inflammatory stimuli and has been shown to have important functions in processes as diverse as proteolytic activation of cytokines, cell death, and membrane repair. Caspase-1-dependent production of the inflammatory cytokines IL-1 and IL-18 has also been implicated in the regulation of appetite, body weight, glucose homeostasis, and lipid metabolism. Consistent with the emerging views of caspase-1 in metabolic regulation, we find that caspase-1-deficient mice have dramatically accelerated triglyceride clearance, without alteration in lipid production or absorption, and resultant decrease in steady-state circulating triglyceride and fatty acid levels. Surprisingly, this effect is independent of IL-1-family signaling, supporting the concept that caspase-1 influences lipid metabolism through multiple mechanisms, not limited to cytokines.