Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats

Abstract

Short-term overfeeding blunts the central effects of fatty acids on food intake and glucose production. This acquired defect in nutrient sensing could contribute to the rapid onset of hyperphagia and insulin resistance in this model. Here we examined whether central inhibition of lipid oxidation is sufficient to restore the hypothalamic levels of long-chain fatty acyl-CoAs (LCFA-CoAs) and to normalize food intake and glucose homeostasis in overfed rats. To this end, we targeted the liver isoform of carnitine palmitoyltransferase-1 (encoded by the CPT1A gene) by infusing either a sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1A activity in the third cerebral ventricle or in the mediobasal hypothalamus (MBH). Inhibition of CPT1A activity normalized the hypothalamic levels of LCFA-CoAs and markedly inhibited feeding behavior and hepatic glucose fluxes in overfed rats. Thus central inhibition of lipid oxidation is sufficient to restore hypothalamic lipid sensing as well as glucose and energy homeostasis in this model and may be an effective approach to the treatment of diet-induced obesity and insulin resistance. IntroductionWorldwide prevalence of obesity has been on the rise, along with its dreaded health consequences: diabetes, vascular diseases, and hypertension (1, 2). Obesity is due to a mismatch between caloric intake and energy expenditure in susceptible individuals. Redundant molecular and neural mechanisms control energy and glucose homeostasis (3-9). Among them, the integration of nutritional cues within the hypothalamus is emerging as a critical step in the metabolic and behavioral adaptation to changes in energy balance. The hypothalamic metabolism of fatty acids can profoundly modify feeding behavior and glucose metabolism (10-13) and has been proposed to function as a biochemical sensor for nutrient availability that in turn exerts negative feedback on nutrient intake (13, 14) and glucose production (10,(15)(16)(17). In this regard, the hypothalamic levels of long-chain fatty acyl-CoAs (LCFA-CoAs) can be increased by enhanced esterification of circulating or central lipids (10, 16) and/or by the local inhibition of lipid oxidation (18). These interventions also result in marked inhibition of feeding behavior and liver glucose fluxes (10,15,16,18) (Figure 1A).Sprague-Dawley rats presented with a highly palatable (lardsupplemented) diet promptly double their daily caloric intake and develop severe hepatic insulin resistance within just 3 days (19,20). In this model the central administration of the long-chain fatty acid (LCFA) oleic acid fails to decrease food intake and glucose production (21). Is defective sensing of lipids within the hypothalamus partly responsible for the defective behavioral and metabolic adap-

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

“…Indeed, central LCFA anorexigenic action and capacity to decrease glucose production are lost after 3 days of overfeeding (4,66). At the cellular level, studies have established that the effect of oleate on neuronal activity is dependent on extracellular glucose concentrations in primary cultures of ventromedial nucleus neurons (67) and in arcuate neurons in brain slices (64).…”

“…The hypothalamus controls energy homeostasis by integrating hormonal and nutrient signals such as long-chain fatty acids (LCFA) 4 and glucose (1). The modulation of glucose homeostasis and food intake by glucose and LCFA relies on the intracellular metabolism of these nutrients.…”

“…The modulation of glucose homeostasis and food intake by glucose and LCFA relies on the intracellular metabolism of these nutrients. Esterification and oxidative metabolism of LCFA has been shown to mediate the effects of LCFA on glucose and energy homeostasis (2)(3)(4)(5), and the actions of glucose in the brain mainly involve changes in the AMP/ATP ratio (6). In peripheral tissues, glucose regulates the partitioning of LCFA-CoA between oxidation and esterification, a process fundamental to glucose regulation of insulin release by the pancreatic beta cell (7).…”

Evidence for Central Regulation of Glucose Metabolism

“…Furthermore, inhibition of LCFA breakdown via selective inhibition of hypothalamic carnitine palmitoyltransferase (CPT1) also led to decreased food intake and EGP in rats, highlighting the role of the hypothalamus as a nutrient sensor and the role of LCFAs as a signal of nutrient abundance (48). Of note, hypothalamic CPT1 inhibition in overfed rats restored hypothalamic lipid sensing and suppression of EGP, suggesting potential therapeutic avenues in obese and overfed models (49).…”

Peripheral tissue–brain interactions in the regulation of food intake

“…Since circulating NEFA can access the brain it is likely that the anorectic action of long-chain fatty acids may play an important role in the regulation of energy balance by acting as a 'nutrient abundance' signal (Lam et al 2005a,b). Impairment of hypothalamic lipid-sensing in rats induces obesity (He et al 2006), as well alterations in plasma glucose (Pocai et al 2006), indicating that this mechanism may be important in the physiological regulation of metabolism and body-weight homeostasis.…”