Question

On the basis of the premise of the thrifty gene hypothesis, predict if the following hypothetical gene variants would be candidate thrifty genes. Explain your answer. a. Acetyl-CoA carboxylase that is insensitive to feedback inhibition by palmitoyl-CoA b. Insulin receptor that has an increased affinity for insulin c. High basal levels of uncoupling protein in liver cells d. A hyperactive lipoprotein lipase on the plasma membrane in adipose cells e. A hyperactive hormone-sensitive lipase on lipid droplets in adipose cells

Short answer

a. Acetyl-CoA carboxylase insensitive to feedback inhibition b. Insulin receptor with increased affinity for insulin c. High basal levels of uncoupling protein in liver cells d. A hyperactive lipoprotein lipase in adipose cells e. A hyperactive hormone-sensitive lipase on lipid droplets in adipose cells Answer: Based on the thrifty gene hypothesis, gene variants a, b, and d could be considered candidate thrifty genes. Variant a encodes an enzyme that promotes continuous lipogenesis, leading to higher levels of fatty acid storage. Variant b encodes an insulin receptor with increased affinity for insulin, promoting better glucose uptake and more efficient energy storage. Variant d encodes a hyperactive lipoprotein lipase, which enhances lipid uptake by adipose cells, increasing their ability to store fatty acids as triglycerides. These gene variants all improve energy storage capacities, aligning with the premise of the thrifty gene hypothesis.

Step-by-step solution

a. Acetyl-CoA carboxylase insensitive to feedback inhibition

This gene variant encodes an Acetyl-CoA carboxylase enzyme that is not inhibited by palmitoyl-CoA. Acetyl-CoA carboxylase is an enzyme involved in fatty acid synthesis; it converts acetyl-CoA to malonyl-CoA, the initial step in fatty acid synthesis. Normally, the enzyme is negatively regulated by feedback inhibition, which is a mechanism that helps maintain a balance between supply and demand. This variant, however, is insensitive to feedback inhibition, leading to continuous lipogenesis, higher levels of fatty acid storage, and increased body fat. Based on the thrifty gene hypothesis, this variant could be a candidate thrifty gene.

b. Insulin receptor with increased affinity for insulin

This gene variant encodes an insulin receptor with increased affinity for insulin binding. Insulin is a hormone essential for glucose uptake and utilization by cells, and it also promotes lipogenesis and glycogenesis, suppressing glucose release from the liver. Higher insulin sensitivity would lead to better glucose uptake by cells, more efficient energy storage, and reduced blood glucose levels, likely resulting in improved metabolic efficiency in times of food scarcity. Based on the thrifty gene hypothesis, this variant could be a candidate thrifty gene.

c. High basal levels of uncoupling protein in liver cells

This gene variant leads to high basal levels of uncoupling proteins in liver cells. Uncoupling proteins are proteins found in the mitochondrial membrane that dissipate the proton gradient generated by the electron transport chain, reducing ATP production and increasing heat generation instead. This effect is associated with a decrease in the efficiency of energy harvesting from supplied substrates, combatting obesity by counteracting its accumulation. From the thrifty gene hypothesis perspective, this variant would likely not be a candidate thrifty gene, as it contributes to lower energy efficiency rather than increased energy storage.

d. A hyperactive lipoprotein lipase in adipose cells

This gene variant encodes a hyperactive lipoprotein lipase on the plasma membrane of adipose cells. Lipoprotein lipase is an enzyme that cleaves lipids from lipoproteins in circulation, enabling fatty acid uptake by cells, particularly adipocytes. A hyperactive lipoprotein lipase would enhance lipid uptake by adipose cells and increase their ability to store fatty acids as triglycerides, boosting overall body fat reserves. Based on the thrifty gene hypothesis, this variant could be a candidate thrifty gene.

e. A hyperactive hormone-sensitive lipase on lipid droplets in adipose cells

This gene variant encodes a hyperactive hormone-sensitive lipase on lipid droplets in adipose cells. Hormone-sensitive lipase is an enzyme that hydrolyzes stored triglycerides, releasing free fatty acids to be used as an energy source. A hyperactive hormone-sensitive lipase would cause more rapid lipolysis, increasing the availability of free fatty acids but potentially promoting frequent usage of stored body fat reserves. From the thrifty gene hypothesis perspective, this variant would likely not be a candidate thrifty gene, as it contributes to the faster breakdown of energy reserves rather than better storage capacities.

Key concepts

Fatty Acid Synthesis

Fatty acid synthesis plays a central role in how the body stores energy. This process involves converting carbohydrates into fatty acids, which are then stored as triglycerides. It's an essential metabolic pathway where acetyl-CoA is transformed into malonyl-CoA by an enzyme called Acetyl-CoA carboxylase.

This enzyme acts as a gatekeeper, deciding when fatty acid production should occur. When it's not regulated and becomes insensitive to signals like palmitoyl-CoA, fatty acid synthesis can proceed unchecked, leading to excess fat storage. Such a trait would support the concept of a 'thrifty gene' as it enables an organism to store more energy during times of plenty.

Insulin Receptor Affinity

Insulin is a hormone that significantly influences metabolism and energy storage. A major role of insulin is to facilitate glucose entry into cells and promote the synthesis of glycogen and fats from sugars. When the insulin receptor on a cell surface has a higher affinity for insulin, this means that the cells become more sensitive to insulin.

This heightened sensitivity could mean the body is more efficient at lowering blood sugar and storing energy, an advantageous factor in times of limited food availability, aligning with the thrifty gene hypothesis. Insulin's relationship with not just glucose but also lipid metabolism underscores its role in harmonizing the body's response to energy intake.

Lipoprotein Lipase Function

Lipoprotein lipase (LPL) is integral in the metabolism of lipoproteins—particles that transport lipids through the bloodstream. This enzyme catalyzes the hydrolysis of triglycerides in lipoproteins, releasing free fatty acids that cells, particularly adipocytes, can store.

A hyperactive LPL would facilitate increased fatty acid uptake by adipose tissue, enhancing the ability to stockpile energy reserves. This trait is in keeping with the thrifty gene hypothesis, suggesting that such a gene variant could be favored in environments where food supply may not be constant or predictable.

Uncoupling Proteins

Uncoupling proteins (UCPs) present in the inner mitochondrial membrane serve to disrupt the proton gradient maintained by the electron transport chain. By doing this, they uncouple oxidative phosphorylation, which means that instead of ATP, heat is generated. This process dissipates energy that would otherwise be used or stored.

High levels of UCPs can lead to 'metabolic inefficiency,' which would seem contrary to the thrifty gene hypothesis that favors efficient use and storage of energy. Therefore, gene variants producing high basal levels of UCPs in organs like the liver could possibly be viewed as 'wasteful' in the context of energy conservation.

Hormone-Sensitive Lipase

Hormone-sensitive lipase (HSL) is an enzyme found within fat cells that breaks down stored triglycerides into fatty acids, a process known as lipolysis. This enzyme allows the body to mobilize stored energy when it is needed.

A hyperactive HSL would lead to lipolysis occurring at a faster rate, releasing stored energy quickly. Considering the thrifty gene hypothesis, this could be seen as disadvantageous, since it leads to rapid depletion of energy stores. Thus, in times of famine, variants that slow down lipolysis could be seen as 'thrifty' due to their role in preserving energy.