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
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.