Identification of a biochemical link between energy intake and energy expenditure

Abstract

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

Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels

“…Because our mitochondrial measurements used succinate as a substrate and thus bypassed complex 1, these data suggest that leptin's effect on hepatic metabolism may be even more profound than we have demonstrated. This finding is also consistent with studies showing that activation of nutrient-sensing pathways can alter NADH dehydrogenase protein levels (40). Further studies analyzing the effect of over-expression or knockdown of these proteins in ob/ob mice will be necessary to further evaluate their role in leptin-mediated substrate oxidation changes.…”

Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role ofPGC1andNRF1

“…Activation of the hexosamine nutrient signaling pathway decreases expression of nuclear-encoded mitochondrial genes in rats (49). Although caloric restriction increases PGC1␣ expression in obese subjects (50), we cannot exclude an additive role for other transcription factors and coactivators in mediating the oxidative metabolism expression phenotype.…”

Insulin Action in the Double Incretin Receptor Knockout Mouse

“…Oxygen consumption (Vo 2 ) and carbon dioxide production (Vco 2 ) were measured using an Oxymax indirect calorimetry system (Columbus Instruments) as described previously (25). Energy expenditure was calculated as described previously (25,26). Respiratory exchange ratio (RER) was calculated as Vco 2 /Vo 2 .…”