the past decade has witnessed a rejuvenated interest in the ability of the central nervous system (CNS) to sense and respond to changes in nutrient availability. This interest has been driven in part by a conceptual framework where the CNS receives signals regarding nutrient availability that are important in the negative feedback control of energy balance and has led to studies demonstrating that direct ventricular or parenchymal administration of nutrients and adiposity hormones drive multiple effectors of energy homeostasis (4). A natural progression of this line of investigation extends to studies evaluating how obesity affects the ability of the CNS to sense and respond appropriately to nutrient excess. A second major impetus for this work is based on demonstrations that obesity is associated with an increased expression of multiple peripheral indexes of inflammation and reduced peripheral insulin sensitivity (3). In this issue of American Journal of Physiology-Endocrinology and Metabolism, Posey et al. (6) develop experimental results revealing a novel linkage between dietary fat and increased CNS expression of inflammatory mediators within the mediobasal hypothalamus (MBH), an area well established to contribute to the negative feedback control of multiple energy regulatory effectors, including feeding behavior, glucose homeostasis, locomotor activity, energy expenditure, sympathetic nervous system activation, and brown adipose tissue thermogenesis. These increases in inflammatory mediators are associated with reductions in local hypothalamic insulin signaling as well as deficits in whole body energy regulatory responses. The data support the interpretation that increased dietary fat engages inflammatory processes in the hypothalamus that undermine the efficacy of central nutrient-sensing mechanisms critical to negative feedback control.
Central administration of the adiposity hormone insulin has been shown to reduce food intake and hepatic glucose production via activation of an insulin receptor signaling cascade involving phosphatidylinositol 3-kinase (PI3K). These effects are diminished in dietary-induced obesity (DIO) and following short-term exposure to high-fat diets, suggesting that increased availability of dietary fats are important in mediating central insulin sensitivity (2). Accumulation of long-chain fatty acyl-CoA has been proposed to reduce insulin sensitivity via alterations in a signaling cascade engaging insulin receptors, IRS proteins, and PI3K. In their study, Posey et al. confirm that DIO produced by chronic overeating of high-fat diet eliminated the ability of central ventricular administration of insulin to reduce food intake, and reduced hypothalamic PI3K signaling of endogenous insulin stimulated by a peripheral glucose challenge. Pair feeding of high-fat diet to the caloric level of standard-chow-fed controls also produced a significant increase in adiposity, accompanied by reductions in the ability of endogenous insulin to drive hypothalamic PKB activation, an index of insulin signaling, and resulted in increased hypothalamic activation of IKKB, a marker for inflammation. Thus dietary fat intake per se, rather than the absolute energetic content of consumed food, may promote obesity, central insulin insensitivity, and hypothalamic inflammation. As high-fat diet exposure typically increases feeding, decreases hypothalamic insulin sensitivity, and increases IKKB, Posey et al. examined the ability of acute pharmacological blockade of hypothalamic IKKB to reverse the dysregulated feeding and insulin-signaling phenotypes in high-fat-fed animals. Acute pharmacological blockade of IKKB attenuated the hyperphagia, IKKB activation, and central insulin insensitivity seen in high-fat-fed rats relative to lean controls without producing any apparent visceral malaise.
High-fat DIO also increased the hypothalamic accumulation of two long-chain acyl-coA species, palmitoyl- and steroyl-CoA, implicated in the development of peripheral insulin resistance. To assess the anatomic specificity and time course of fatty acid action itself in the hypothalamus, infusions of palmitoyl-CoA were administered directly into the third ventricle over a period of 6 h in lean, standard-chow-fed animals. These infusions increased hypothalamic palmitoyl-CoA levels relative to vehicle-treated controls, supporting the relationship between increased cerebrospinal fluid (CSF) fatty acid availability and increased hypothalamic long-chain CoA levels. Elevated long-chain CoA levels were associated with increased hypothalamic IKKB phosphorylation and decreased hypothalamic PI3K activity in response to central insulin challenges. Thus, increased central availability of dietary fatty acids in obesity may act at the level of hypothalamic neurons to increase cellular inflammation and reduce insulin sensitivity. The acute effects of increased fatty acid availability on hypothamalic insulin signaling and the acute improvement in hyperphagia, inflammation, and insulin signaling following local IKKB inhibition support a novel rapid role for dietary fats activating inflammatory mechanisms to interfere with behavioral and physiological negative feedback regulation of energy availability during high-fat feeding.
These data complement and extend recent work of De Souza et al. (2), demonstrating that consumption of high-fat diets alters the expression of hypothalamic mRNA encoding inflammatory response proteins and impair the ability of central insulin infusions to drive hypothalamic insulin signaling and reduce food intake. Consistent with the present work, they also found that acute central pharmacological inhibition of c-Jun NH2-terminal kinase, a marker of inflammation, reduced high-fat diet hyperphagia and attenuated insulin signaling.
Although the current results significantly advance our understanding of central nutrient sensing capabilities, there remains important work to be done to establish the physiological role of CNS dietary fatty acids in driving behavioral and physiological effectors of energy balance. High-fat diets failed to elevate hypothalamic oleyl-CoA levels, a surprising finding given the demonstration that brain ventricle infusion of the long-chain fatty acid oleic acid reduces food intake and suppresses hepatic glucose production (5). This apparent discrepancy raises the more general issue of the physiological relationship between dietary fatty acid availability and evidence of central nutrient sensing. Specifically, 1) how do CSF fatty acid levels change acutely following high-fat feeding; 2) what is the time course of hypothalamic long-chain CoA increase upon increases in CSF fatty acid level; and 3) what is the temporal association between these changes, hypothalamic long-chain CoA content, and hypothalamic markers of inflammation? Fatty acid infusions increased inflammation within 6 h, and the pharmacological blockade of IKKB increased high-fat food intake in DIO within 4 h, suggesting that there is at least an acute phase of inflammation linked directly to changes in local fatty acid availability.
In addition, nutrient-sensing sites critical for the central regulatory responses to increased nutrient availability remain to be fully determined. It is not clear from present and published work that either ventricular administration of fatty acids or pharmacological blockade of inflammatory mediators solely engages hypothalamic neurons. While agouti-related peptide (AgRP) neuronal specific blockade of IKKB in mediobasal hypothalamus blocks high-fat diet-induced reductions in central insulin sensitivity (7), the sites where ventricular insulin administration acts to affect hypothalamic IKKB remain uncertain, and may not be intrinsic to the MBH. Additional study will be required to determine the extent to which the effects of fatty acids are specific to the actions of insulin within the MBH or are indirect consequences of altered insulin signaling at multiple hypothalamic and extrahypothalamic neuronal sites that project to the MBH.
The current results are particularly compelling in that fat diet hyperphagia and impaired insulin signaling in DIO can be acutely improved by pharmacological blockade of IKKB activation. Such data are not susceptible to concerns that chronic compensatory responses may mediate the beneficial metabolic effects of constitutive AgRP neuronal knockdown of IKKB (7). Although Zhang et al. (7) also found that hypothalamic lentiviral downregulation of IKKB in AgRP neurons reduced chronic high-fat diet intake and weight gain at 3 wk postinjection, the present data speak to a much more rapid feeding-inhibitory response. Thus, a second front for further exploration is the investigation of intra- and extracellular effectors mediating the present rapid changes. In terms of understanding the downstream neural circuitry underlying the feeding-inhibitory response to pharmacological IKKB blockade, it would be important to know the degree to which meal size and frequency were affected. Acute changes in meal size have been attributed to forebrain influences on caudal brainstem neurons of the nucleus of the solitary tract. These neurons have been shown to integrate descending hypothalamic signals with those arising from gut afferents responsive to postoral meal-related stimuli, such as the present of nutrients in the gut and the gut peptide cholecystokinin (1). Comparisons of meal patterns and patterns of forebrain-hindbrain neuronal activation following acute vs. chronic hypothalamic IKKB inhibition have the potential to reveal distinct nutrient-sensing pathways mediating feeding, energy balance, and glucose homeostasis during DIO.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R01 DK-047208 and DK-020541 and the Skirball Institute for Nutrient Sensing to G. J. Schwartz.
- Copyright © 2009 the American Physiological Society