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Cellular sensors of feast and famine
Eric Ravussin
Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana, 70808-4124, USA.
Phone: (225) 763-3186; Fax: (225) 763-3030; E-mail: Ravusse@pbrc.edu.
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Published June 15, 2002 - More info
J Clin Invest. 2002;109(12):1537–1540. https://doi.org/10.1172/JCI16045.
© 2002 The American Society for Clinical Investigation
In response to changes in environmental conditions, animals and humans alike can initiate physiological regulatory mechanisms to assure survival. For example, when food is scarce, the body becomes “thrifty”, and conversely, when it is abundant, physiological “unthrifty” mechanisms are initiated. Recent work has uncovered novel cellular mechanisms of fuel sensing that contribute to these shifts and has established a potential relationship between these responses and the common metabolic phenotype of insulin resistance.
The first such mechanism to be identified depends on malonyl Co-A, which allosterically inhibits carnitine palmitoyl transferase (CPT1). Because this enzyme controls mitochondrial uptake, and hence oxidation, of long-chain fatty acyl-CoAs (see Ruderman for review, ref. 1), malonyl-CoA can act as a fuel sensor to regulate the rate of fatty acid oxidation in muscle (Figure 1). Ten years ago, Marshall et al. (2) suggested that another fuel-sensing mechanism, this one dependent on the hexosamine biosynthesis pathway (blue arrows in Figure 1), mediates the cellular response to excess environmental glucose. These authors proposed that metabolism of glucose by this route, which typically represents 1-3% of total glucose metabolism, generates a cellular satiety signal that leads to decreased glucose uptake by insulin-sensitive cells.
Figure 1Two cellular fuel-sensing pathways. The hexosamine biosynthesis pathway and the malonyl Co-A system are proposed to modulate energy consumption by muscle and other tissues in response to changing levels of metabolic fuels. Following its entry into the cell via the glucose transport system, glucose is phosphorylated into glucose-6-phosphate (G-6-P), which is primarily utilized by the pathways of glycogen synthesis and glycolysis. Only 1–3% of the glucose entering the cells is diverted to glucosamine-6-phostate by the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT) (blue arrows). The end product of this pathway, uridinediphosphoglucose-N-acetylglucosamine (UDP-GlcNAc) serves as substrate for virtually all glycosylation pathways in the cells. Glucosamine enters the pathway directly after the rate-limiting step of GFAT, therefore mimicking a signal of excess glucose or nutrient. The second fuel-sensing pathway is that of malonyl-CoA. Increased cytosolic citrate from both the Krebs cycle and beta-oxidation contribute to increased Acetyl-CoA. Acetyl-CoA is the precursor of malonyl-CoA, a conversion that involves acetyl-CoA carboxylase 2 (ACC2). The primary role of malonyl-CoA is to regulate the rate of fat oxidation via its allosteric inhibition of carnitine palmitoyl transferase (CPT1), the enzyme responsible for converting long-chain fatty acyl-CoA into long-chain acyl-carnitine. Because the availability of Acetyl-CoA and the activity of ACC2 can each influence the concentration of malonyl-CoA, both can alter the balance between fat storage and fat oxidation.
In this issue of the JCI, Obici et al. (3) propose that the hexosamine pathway is not only involved in glucose metabolism and insulin resistance, but may also be one of the biochemical links between nutrient availability and cellular energy metabolism. The activation or inhibition of this fuel sensing pathway may, therefore, play an important role in the regulation of energy balance. However, their present data raise significant questions about the role of transcriptional regulation in the adaptive response to energy surfeit.
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Energy balance and the “thrifty genotype”
Historically, most human populations have evolved in environments in which large amounts of physical effort were required to obtain food in limited supply. Thus, it is not surprising that the human genome harbors many genes that predispose to positive energy balance and obesity and fewer that protect against the effect of affluence. The tendency of populations to gain weight under current conditions of plenty should therefore be considered as a normal physiologic response to what has been called an “obesigenic” environment. Large differences in individuals’ propensity to weight gain persist in the face of this general trend (4, 5), probably because the “thrifty genotype”, as James Neel termed it, is distributed unevenly among individuals (6, 7).
One hundred years ago, Neumann made the seminal observation that the increase in body weight in response to overfeeding is not proportional to the excess ingested energy (8). To explain this discrepancy, he hypothesized that some of the energy ingested, in excess of normal requirements, was dissipated as heat or “Luxuskonsumption”. This was the first description of what is now referred to as adaptive thermogenesis. Over the past five decades, scientists have tried to identify the mechanisms underlying the variability in adaptive thermogenesis and its consequence on weight gain in response to overfeeding. First, at the whole-body level, it became clear that energy surfeit can be sensed and that signals are sent to central controllers. These controllers then orchestrate a physiological response, which tends to limit food intake and increase energy metabolism (Figure 2). This feedback model, originally proposed by Bray (9), still represents the working hypothesis that is used to explain the large variability in body weight gain in response to excess energy intake. According to this model, in response to overfeeding, the gastro-intestinal tract and the adipose tissue, among others, provide endocrine and neural signals to brain controllers of energy balance. In response, these controllers engage a series of efferent neural and neuroendocrine signals that are specifically geared to counteract the excess caloric intake. These signals eventually decrease appetite and/or increase energy expenditure, thus causing a decrease in the energy stored in the body. Conversely, during periods of food restriction, opposing signals protect the body against energy loss by increasing hunger and food-seeking behaviors and decreasing energy expenditure. Any component of this feedback loop can influence the robustness of the adaptive response. More recent research has focused on the potential molecular mechanisms that explain this response to fuel availability at the cellular level.
Figure 2The negative feedback model for the regulation of body weight. In this model, peripheral signals from energy stores (adipose tissue, muscle, and liver) as well as hormonal and gastrointestinal signals act on the central controllers in the brain, indicating the state of the external and internal environment as they relate to food, metabolic rate, and activity behaviors. In turn, the central controllers integrate these signals and transduce these messages into efferent signals governing the behavioral search for the acquisition of food, as well as modulating its subsequent deposition into energy storage compartments, such as adipose tissue, liver, and muscle. Afferent signals, efferent signals, and central controllers can all be influenced by an organism’s genetic makeup, hence the inter-individual variability in weight change in response to a perturbed energy balance.
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