The hypothalamus and other regions within the central nervous system (CNS) link the sensing of nutrients to the control of metabolism and feeding behavior. Here, we report that intracerebroventricular (ICV) administration of the long-chain fatty acid oleic acid markedly inhibits glucose production and food intake. The anorectic effect of oleic acid was independent of leptin and was accompanied by a decrease in the hypothalamic expression of neuropeptide Y. The short-chain fatty acid octanoic acid failed to reproduce the metabolic effects of oleic acid, and ICV coadministration of inhibitors of ATP-sensitive K ؉ channels blunted the effect of oleic acid on glucose production. This is the first demonstration that fatty acids can signal nutrient availability to the CNS, which in turn limits further delivery of nutrients to the circulation. Diabetes 51:271-275, 2002 E xcessive consumption of nutrients with high caloric density is largely responsible for the epidemic of obesity and type 2 diabetes in the western hemisphere and in developing nations (1,2). The association of nutrient excess and obesity with type 2 diabetes is largely mediated via their negative impact on intermediary metabolism and insulin action (1-3). Control of metabolism and food intake in response to nutrients occurs partly at the level of hypothalamic nuclei (3-5). In this regard, macronutrients, such as carbohydrates and lipids, regulate the circulating levels of leptin and insulin (3,6,7), which in turn modulate appetite, energy expenditure, and intermediary metabolism mainly via their hypothalamic receptors (Fig. 1A) (3-5). However, central nervous system (CNS) neurons may also sense nutrients directly via metabolic signaling (8). In this regard, the potential role of CNS lipid metabolism in the control of appetite is supported by the potent anorectic property of fatty acid synthase inhibitors (9,10). Further- FIG. 1. Rapid effects of ICV oleic acid on plasma insulin and glucose levels.A: Hypothesis on the negative feedback mechanisms regulating circulating nutrients. There are two main sources of circulating nutrients: intake and absorption of food (Food) and hepatic production of glucose and lipids (Liver). Increased levels of plasma glucose and lipids regulate hypothalamic efferent pathways via their stimulatory effects on insulin and leptin biosynthesis and secretion. The activation of these central responses leads to decreases in food intake and in hepatic output of glucose and lipids. It is proposed herein that circulating nutrients may also directly signal the nutritional status to the hypothalamus and may therefore play a role in this feedback system. B: Schematic representation of the experimental procedures. Surgical implantation of ICV cannulae was performed on day 1 (ϳ3 weeks before the in vivo study). Full recovery of body weight and food intake was achieved by day 7. Surgical implantation of IV catheters was performed on day 14. Finally, on day 21, ICV infusions were started and blood chemistries, food intake, and/or insulin ac...

In common forms of obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia coexist. Here, we demonstrate rapid induction of insulin and leptin resistance by short-term overfeeding. After 3 and 7 days on the assigned diet regimen, rats were tested for their biological responses to acute elevations in plasma insulin and leptin concentrations. Severe resistance to the metabolic effects of both leptin and insulin ensued after just 3 days of overfeeding. During the insulin clamp studies, glucose production was decreased by ϳ70% in control rats and 28 -53% in overfed rats. Similarly, leptin infusion doubled the contribution of gluconeogenesis to glucose output in control rats but failed to modify gluconeogenesis in overfed animals. These findings demonstrate a paradoxical and rapid collapse of the leptin system in response to nutrient excess. This partial failure is tightly coupled with the onset of insulin resistance. Diabetes 50:2786 -2791, 2001 H yperphagia and elevated levels of both insulin and leptin are common features of obesity (1)(2)(3)(4)(5)(6)(7)(8). This is paradoxical because leptin is a potent inhibitor of feeding (9 -15) and is expected to decrease insulin levels via improved insulin action (16 -21) and inhibition of insulin secretion (22). To reconcile these findings, it has been proposed that obesity is associated with resistance to the biological effects of both insulin and leptin (1-8). However, although it is generally assumed that leptin resistance contributes to hyperphagia (1,4,6,7), it is also possible that hyperphagia may induce leptin resistance and other metabolic sequelae of obesity. This rapid adaptation to increased energy availability may be designed to curtail the leptin system in order to facilitate storage of nutrients into lipid stores (1,3,(23)(24)(25). This may be accomplished by restraining leptin biosynthesis (23-25) and/or by inducing leptin resistance (1,(3)(4)(5)(6)24,26). These mechanisms would be particularly well developed in individuals or animals predisposed to weight gain and diabetes (1,11,24,25,27). Consistent with the "thrifty genotype" hypothesis, this sequence of events would be tightly coupled to the onset of insulin resistance (1,11,24,28).In addition to its anorectic actions, leptin is also a potent modulator of biochemical pathways and metabolic fluxes (17-19,29 -32). In particular, we have shown that acute administration of leptin to postabsorptive rats caused a marked redistribution of intrahepatic glucose fluxes, with a marked increase in the relative contribution of gluconeogenesis and a parallel decrease in the contribution of glycogenolysis to hepatic glucose fluxes (19,32). These acute metabolic effects of leptin can be utilized to evaluate leptin sensitivity as a measurable biological response to an acute challenge with the hormone. Recent evidence in rodents (25) and humans (27) indicate that inadequate early increase in leptin secretion and biosynthesis in response to overeating may also play a role in the development of obesity and glucose intole...

Central administration of the long-chain fatty acid oleic acid inhibits food intake and glucose production in rats. Here we examined whether short term changes in nutrient availability can modulate these metabolic and behavioral effects of oleic acid. Rats were divided in three groups receiving a highly palatable energy-dense diet at increasing daily caloric levels (below, similar, or above the average of rats fed standard chow). Following 3 days on the assigned diet regimen, rats were tested for acute biological responses to the infusion of oleic acid in the third cerebral ventricle. Three days of overfeeding virtually obliterated the metabolic and anorectic effects of the central administration of oleic acid. Furthermore, the infusion of oleic acid in the third cerebral ventricle failed to decrease the expression of neuropeptide Y in the hypothalamus and of glucose-6-phosphatase in the liver following short term overfeeding. The lack of hypothalamic responses to oleic acid following short term overfeeding is likely to contribute to the rapid onset of weight gain and hepatic insulin resistance in this animal model.Obesity and type 2 diabetes mellitus (DM2) 1 share several metabolic features, which include insulin resistance (1-3). The incidence of obesity and DM2 has risen significantly in developed and developing countries. For example, in the United States alone there has been a significant increase in the prevalence of obesity among both children and adults over the last 10 years (4, 5). Consumption of high calorie diets and sedentary lifestyles play major roles in this trend (2,4,6). Similarly, exposure to palatable diets with high caloric density (high in fat) induces a variable degree of weight gain and insulin resistance in mice (7,8), rats (9 -11), pigs (12), dogs (13), and monkeys (14).Evolutionary pressures may have favored the selection of genes, which maximize energy storage when food availability is high (15-18). We and others have proposed that a rapid increase in caloric intake initiates a "tug of war" between peripheral "anabolic signals" (19) and hypothalamic "catabolic signals" (20 -26). The effects of hormones, such as leptin (27-31) and insulin (24,25,32,33), and perhaps nutrients, such as fatty acids (21,23,26), within the hypothalamus initiate a negative feedback, which includes restraint on food intake, stimulation of energy expenditure, and decreased output of nutrients from endogenous sources (mainly from the liver). Animals and humans may be susceptible to weight gain and altered metabolic regulation when this negative feedback is disrupted. The rapid onset of leptin resistance in rodent models of voluntary overfeeding provides initial support for this theory (34, 35).Here we test the hypothesis that short term increase in caloric intake rapidly induces resistance to the central effects of the long-chain fatty acid, oleic acid (OA). Thus, we examined whether changes in nutritional status lead to alterations in the central effects of OA on feeding behavior and glucose production. EXPERI...

Voluntary overfeeding rapidly induces resistance to the effects of systemic insulin and leptin on liver glucose metabolism. To examine whether central administration of recombinant leptin can restore leptin and insulin action on liver glucose fluxes, we infused leptin in the third cerebral ventricle of conscious overfed rats during pancreatic-insulin clamp studies. The effect of leptin on the phosphorylation of the signal transducer and activator of transcription-3 in the arcuate nuclei of the hypothalamus was similar in animals fed a regular diet or a high-fat diet for 3 days. The infusion of leptin in the third cerebral ventricle markedly inhibited glucose production in rats fed a high-fat diet mainly by decreasing glycogenolysis. The inhibition of glycogenolysis was sufficient to normalize glucose production and was accompanied by leptin-induced decreases in the hepatic expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Thus central administration of leptin rescues the hepatic insulin resistance induced by short-term hyperphagia. Diabetes 54:3182-3189, 2005 L eptin is an adipocyte-derived hormone that can modulate food intake and hepatic insulin action (1-4). Circulating leptin is transported into the brain via a saturable transport system located at both the endothelium and choroids plexus (5,6). After crossing the blood-brain barrier (BBB), the actions of leptin are mediated mainly through the long form of the leptin receptor (OB-Rb) which is the only isoform capable of activating the JAK-signal transducer and activator of transcription (STAT) pathway (7-9). Genetic deficiency of leptin (ob/ob mice) as well as mutations in the leptin receptor (db/db mice, Zucker fatty [fa/fa] rats) lead to obesity and diabetes (10). In humans, rare cases of monogenic obesity syndromes have also been described previously (11).Obese individuals have severe insulin resistance with high circulating levels of both insulin and leptin (12,13). In this regard, the failure of the elevated leptin levels to restore normal energy and metabolic homeostasis is commonly viewed as evidence for leptin resistance. Multiple reports in rodents have highlighted the severe impairment in the anorectic action of leptin in high-fat-fed models (14 -17). This acquired form of leptin resistance has been ascribed to defects at the level of leptin transport into the central nervous system (CNS) and/or at the level of leptin signaling within the CNS. In this regard, Van Heek et al. (16) reported that diet-induced obese mice develop peripheral but not central resistance to leptin, whereas El Haschimi et al. (14) and Munzberg et al. (15) observed that two defects contribute to their leptin resistance, impaired leptin transport in the brain, and decreased ability of leptin to activate STAT3 in the arcuate nucleus of the hypothalamus.Importantly, there is growing evidence that leptin also plays an important role in the modulation of metabolic fluxes and insulin action (18). For example, that leptin reverses insulin resistance and d...

The increasing prevalence of obesity in industrialized societies is largely due to excessive caloric intake. However, there are major variations in the extent to which an individual alters energy metabolism and gains weight in response to increased caloric intake (1, 2). Furthermore, base-line energy expenditure is a strong predictor of future weight gain (3). The physiological basis for individual variability in energy expenditure is still poorly understood. A sustained increase in food intake activates adipostatic responses, which tend to limit lipid storage by enhancing energy expenditure (4) and inhibiting appetite (5). However, consistent with Neel's "thrifty genotype" hypothesis, the increased availability of nutrients may also have biological effects designed to increase the efficiency of energy storage by limiting fuel oxidation and ATP production (6). Indeed, cells can monitor nutrient availability via the activation of nutrient-sensing pathways such as the hexosamine biosynthesis pathway (HBP) (7, 8). The final step in HBP is the formation of UDP-N-acetylglucosamine (UDP-GlcNAc), which is a product of intracellular glucose metabolism and is a main substrate for glycosylation of proteins. Many cytoplasmic and nuclear proteins are glycosylated on their serine and/or threonine residues by the addition of a single molecule of O-linked β-N-acetylglucosamine (O-Glc-NAc) (9). In particular, several transcriptional factors undergo this type of rapid modification, which causes changes in their activity and/or in their stability (Figure 1a) (10-13). A prominent role of HBP in the regulation of energy balance is suggested by its role in the modulation of leptin expression and insulin action in adipose tissue and skeletal muscle (7, 8, 14-17). Methods Animals. Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Massachusetts, USA) were housed in individual cages and subjected to a standard 12-hour light-dark cycle. All rats received standard chow ad libitum (catalog no. 5001; Purina Mills Inc., St. Louis, Missouri, USA), with 59% calories provided by carbohydrates, 20% by protein, and 21% by fat. Seven days prior to the in vivo studies, all rats underwent insertion of indwelling catheters into the right internal jugular vein and the left carotid artery as described previously (14). In the shortterm overfeeding experiments, rats were allowed to eat ad libitum a palatable high-fat diet (catalog no. 9389; Purina Mills Inc.) with 45% calories provided by carbohydrates, 33% by fat, and 22% by protein for 3 days prior to the clamp studies as previously described (18). Control rats received a daily allowance of palatable high-fat diet restricted at 80% of their pre-intervention caloric intake. Clamp studies. All in vivo studies were performed in awake, unstressed rats fasted for 6 hours, using a euglycemic-hyperinsulinemic clamp technique, as described previously (14). GlcN (30 µmol/kg/min, n = 11) or saline

Obesity is the result of an imbalance between energy intake and energy expenditure. Using high-density DNA microarrays and Northern analyses, we demonstrated that the activation of a nutrient-sensing pathway, the hexosamine biosynthesis pathway (HBP), rapidly decreased the expression of a cluster of nuclear-encoded mitochondrial genes involved in skeletal muscle oxidative phosphorylation. Conversely, the expression of uncoupling protein-1 and of the same mitochondrial genes was increased in brown adipose tissue. Most important, these transcriptional changes were accompanied by a marked decrease in whole-body energy expenditure. Short-term overfeeding replicated this transcriptional pattern, suggesting that this adaptation to nutrient abundance occurs under physiological conditions. Thus, the activation of the HBP by nutrients represents a biochemical link between nutrient availability, mitochondrial proteins, and energy expenditure, and it is likely to play an important role in the regulation of energy balance

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