We validate the use of 1H magnetic resonance spectroscopy (MRS) to quantitatively differentiate between adipocyte and intracellular triglyceride (TG) stores by monitoring the TG methylene proton signals at 1.6 and 1.4 ppm, respectively. In two animal models of intracellular TG accumulation, intrahepatic and intramyocellular TG accumulation was confirmed histologically. Consistent with the histological changes, the methylene signal intensity at 1.4 ppm increased in both liver and muscle, whereas the signal at 1.6 ppm was unchanged. In response to induced fat accumulation, the TG concentration in liver derived from 1H MRS increased from 0 to 44.9 ± 13.2 μmol/g, and this was matched by increases measured biochemically (2.1 ± 1.1 to 46.1 ± 10.9 μmol/g). Supportive evidence that the methylene signal at 1.6 ppm in muscle is derived from investing interfascial adipose tissue was the finding that, in four subjects with generalized lipodystrophy, a disease characterized by absence of interfacial fat, no signal was detected at 1.6 ppm; however, a strong signal was seen at 1.4 ppm. An identical methylene chemical shift at 1.4 ppm was obtained in human subjects with fatty liver where the fat is located exclusively within hepatocytes. In experimental animals, there was a close correlation between hepatic TG content measured in vivo by 1H MRS and chemically by liver biopsy [ R = 0.934; P < .0001; slope 0.98, confidence interval (CI) 0.70–1.17; y-intercept 0.26, CI −0.28 to 0.70]. When applied to human calf muscle, the coefficient of variation of the technique in measuring intramyocellular TG content was 11.8% in nonobese subjects and 7.9% in obese subjects and of extramyocellular (adipocyte) fat was 22.6 and 52.5%, respectively. This study demonstrates for the first time that noninvasive in vivo 1H MRS measurement of intracellular TG, including that within myocytes, is feasible at 1.5-T field strengths and is comparable in accuracy to biochemical measurement. In addition, in mixed tissue such as muscle, the method is clearly advantageous in differentiating between TG from contaminating adipose tissue compared with intramyocellular lipids.

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...

Pravastatin, simvastatin, and atorvastatin significantly decreased levels of hs-CRP. These data support an anti-inflammatory effect of these drugs.

We asked whether the well known starvation-induced impairment of glucose-stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acidtreated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal ␤ cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences. ( J. Clin. Invest. 1996. 97:2728-2735.)