Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the utilization of fat as an energy source during starvation and is the molecular target for the fibrate dyslipidemia drugs. Here, we identify the endocrine hormone fibroblast growth factor 21 (FGF21) as a mediator of the pleiotropic actions of PPARalpha. FGF21 is induced directly by PPARalpha in liver in response to fasting and PPARalpha agonists. FGF21 in turn stimulates lipolysis in white adipose tissue and ketogenesis in liver. FGF21 also reduces physical activity and promotes torpor, a short-term hibernation-like state of regulated hypothermia that conserves energy. These findings demonstrate an unexpected role for the PPARalpha-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation.

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.)

Low density lipoprotein receptor-related protein (LRP) is a recently described cell-surface protein of 4544 amino acids that contains reiterated sequences found in the 839-amino acid receptor for low density lipoprotein (LDL). In the current studies, we purified LRP from rat liver, prepared polyclonal antibodies that recognize the extracellular domain, and demonstrated an immunoreactive protein of %600 kDa in human fibroblasts. The function of this LRP was studied in mutant human fibroblasts that do not produce LDL receptors.The mutant cells were incubated with fl-migrating very low density lipoprotein (J3-VLDL) that was isolated from cholesterol-fed rabbits and artificially enriched with apoprotein (apo) E by incubation in vitro with human apo E produced in a bacterial expression system. The apo E-enriched f-VLDL, but not unincubated fl-VLDL, stimulated incorporation of [14C]-oleate into cholesteryl ["4Cioleate 20-to 40-fold in the mutant cells. This stimulation was blocked by chloroquine, suggesting that such stimulation resulted from receptor-mediated uptake and lysosomal hydrolysis of the cholesteryl esters in apo Eenriched fl-VLDL. Stimulation of cholesterol esterification was blocked by the antibody against LRP, but not by an antibody against the LDL receptor. Unlike the LDL receptor, the amount of LRP was not reduced when cells were incubated with oxygenated sterols. We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E.Lipoproteins that contain apoproteins (apo) B or E are removed from plasma by binding to high-affinity receptors on the liver and extrahepatic tissues. At least two receptors play a role (1). The low density lipoprotein (LDL) receptor binds LDL, which contains only apo B-100. It also binds apo E-containing remnants of chylomicrons and very low density lipoproteins (VLDL) that are produced by lipoprotein lipase. Approximately 70% ofLDL receptors are located in the liver, and the rest are found in adrenal gland, ovary, and other extrahepatic tissues (1).The existence of a second receptor was suggested by observations in patients with homozygous familial hypercholesterolemia (FH) and WHHL rabbits in whom LDL receptors are genetically defective (2). Although VLDL remnants and LDL accumulate in blood of affected individuals, chylomicron remnants do not (3). WHHL rabbits clear chylomicron remnants normally (4), and they also rapidly clear an appreciable fraction of large VLDL particles from blood (5). These observations suggest that the second receptor is specific for apo E-containing chylomicron remnants and large VLDL. Repeated attempts to define this receptor biochemically have been unsuccessful.A major advance has recently come from the work of Herz et al. (6), who used homology cloning to isolate a cDNA for an LDL receptor-related protein (LRP). The LRP resembles the LDL receptor in containing two types of cysteine-rich repeats, one related to complement proteins and the other related ...

SUMMARY Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2−/− mice develop severe lipodystrophy affecting both white and brown adipose tissue, severe insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased ~4-fold in Agpat2−/− mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2−/− mice suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by ~50% in Agpat2−/− mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a novel monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2−/− mice.

Cross-sectional studies in human subjects have used 1 H magnetic resonance spectroscopy (HMRS) to demonstrate that insulin resistance correlates more tightly with the intramyocellular lipid (IMCL) concentration than with any other identified risk factor. To further explore the interaction between these two elements in the rat, we used two strategies to promote the storage of lipids in skeletal muscle and then evaluated subsequent changes in insulin-mediated glucose disposal. Normal rats received either a low-fat or a high-fat diet (20% lard oil) for 4 weeks. Two additional groups (lowfat + etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade of enzyme activity in liver and skeletal muscle.