# Metabolism & Nutrition – Lecture 2: Energy metabolism

The second lecture in the Metabolism & Nutrition course was delivered by Bert Groen, from the department of Pediatrics. [It was originally planned after the Fat metabolism lecture, which was rescheduled for the day after, due to Janine’s absence the previous day.] The unifying thread in this lecture is how metabolic pathways that have evolved for efficient energy use and storage pose serious health threats in the current age of abundant calory-dense food.

## Obesity & diabetes

A core physiological principle is that homeostatis is important for maintaining functional integrity—obesity can be seen as a deviation of such a steady state. Consumption of high-fat foods acts on central reward pathways such that palatability drives over-consumption—intake beyond the requirements for homeostasis. Nutrient load to homeostatic circuits in the CNS increases, leading to cellular leptin and/or insulin resistance. Even more food is consumed as the sensitivity to satiation signals decreases, and a vicious feed-forward cycle is created, leading to hyperphagia and often ending in obesity.

Some perspective on societal costs of hyperphagia: 8.21% of adults in the Netherlands suffer from diabetes. Compared with fatal traffic accidents (661 in 2011), the annual death toll of diabetes is huge (7821k in 2012).

Interestingly, insulin-resistance can be developed in response to a high-fat diet. Apparently, fat is burned in preference to sugar, leaving the blood sugar untouched when sufficient free fatty acids are available. The amount of free fatty acids in the blood is always kept at a steady state, within a very narrow range. Higher concentrations are toxic. But, according to Bert, it is unknown why blood sugar is not kept as strictly at low concentrations as free fatty acids are.

## Daily energy expenditure

Energy expenditure consist of the basal metabolic rate + the energy required for activity. Basal metabolic rate (BMR) is the energy expenditure during rest, at normal temperatures. Average energy requirements are ~ 2000–2400 kcal / day. Average energy requirement for ♀♀ < ♂♂.

### Harris Benedict Equation for calculating energy demand

• Step 1. Calculate BMR using the following equation (or online): $$\begin{array}{l l} \text{BMR} = 10 \times \text{weight (kg)} + 6.25 \times \text{height (cm) } – 5 \times \text{age (yrs)} + 5 \quad & \text{if ♂} \\ \text{BMR} = 10 \times \text{weight (kg)} + 6.25 \times \text{height (cm) } – 5 \times \text{age (yrs) } – 161\quad & \text{if ♀} \\ \end{array}$$

My weight avarages around ~75kg, and I’m usually somewhere between 181–182cm long. At 32, this puts me at a BMR of 1785.9 kcal day⁻¹.

• Step 2. Multiply BMR with a value between 1.2 (for individuals who don’t exercise) and 1.9 (for indivuals who heavily exercise twice daily). These multipliers don’t apply to very muscular or very fat individuals, since the lean body mass is not calculated.

Although I consider myself too muscular for these estimates, let’s multiply my BMR with 1.725 (for individuals who exercise 6–7 times / week): $$1785.9 \times 1.725 = 3080.68 \text{ kcal day}^{-1}$$.

These numbers being as arbitrary as they are, I wonder how many more calories I stuff through my mouth every day. The eatmeter tutorial will tell.

## Fat metabolism

Energy content of different macronutrients:

Macronutrient class E (kcal/kg)
Carbohydrates 4000
Proteins 4000
Fats 9000

Fat is a high energy food (9000 kcal/kg » 4000 kcal/kg). Also, fat absorption is very efficient, as has been shown by Wierdsma et al. in Hum Nutr Diet. 2013 27 (Suppl. 2), 57–64. The body doesn’t downregulate fat absorption at increasing concentrations, and nobody has as of yet figured out how to put a brake on fat absorption, while such a discovery would hold potential to be developed into a silver bullet for weight loss and control. Contrast this, for example, with cholesterol absorption, which gets downregulated when much cholesterol is absorbed.

## Fuel reserves

Available fuel reserves in a typical 70kg man (adapted from Cahill 1976, tbl. 1)[1]:

Glycogen or glucose ‘Mobilisable’ protein Triglyceride g kcal g 15 60 0 0 5 45 100 400 100 400 50 450 2 8 0 0 0 0 300 1200 6000 24000 50 450 20 80 10 40 15000 135000

Little glycogen is stored in the body, only about enough to last a day-long fast. Longer fasting requires the energy available in triglycerides.

Not all energy needs can be met with triglycerides, though. If the glucose store is depleted, muscle tissue will have to be catabolized to produce ketons, which, unlike fatty acids, can be oxidized by brain cells. Red blood cells, because they lack mitochondria, require glucose as well. That is why the Atkinson diet, which substitutes carbohydrates with fat and protein, will lead to muscle loss. The glucose requirement to fuel the brain and the blood is ~200 g day ⁻¹. Normally, in the human body, blood $$\text{[glucose]} \approx 5\text{mM}$$.

(See Figure 1 & 2 in Dynamic Adaptation of Nutrient Utilization in Humans from the Nature Education series 3(9):8 by T. El Bacha, M. Luz & A. Da Poian for a nice schematics overview of the metabolic pathways of different types of fuel molecules.)

## Running on sugar

When running, glucose is converted to pyruvate by glycolysis in the muscle’s cytoplasm. As long as there is sufficient O₂, the pyruvate is converted to CO₂ H₂O and ATP in the mitochindia. When O₂ runs low, during the last seconds of a sprint, pyruvate is converted directly in the cytoplasm, into lactate.

Some possible fates of glucose. Adapted from Berg 2012, Fig. 16.1.

Glocuse transporters GLUT1–GLUT4 each have different transport speeds, expressed in different $$K_M$$ values. $$K_M$$ is the substrate concentration at which the transport speed is $$1/2V_{max}$$, i.e. with a low $$K_M$$, an enzyme is quickly saturated. Tissue-specific glucose transport rates are realized by expression of different GLUT transporters. Note that glucose absorption is not regulated in brain cells, because the brain has to keep [Glucose] ≥ 2 mM.

Full glycolytic pathway. Adapted from Berg 2012, Fig. 16.2.

### Regulation of glycolysis

At rest, in muscle tissue, glycolysis is inhibited due to a negative feedback on Hexokinase by increasing [Glucose 6-phosphate], its product. [Berg 2012, Fig. 16.19 part 1] (In the liver, this feedback doesn’t exist.) Further down the pathway, the PFK and Pyruvate kinase enzyme activities are inhibited by increasing [ATP]/[AMP] ratio. ([ATP]/[AMP] ratios are used as a cellulair energy sensing mechanism.) During exercise, decreasing [ATP]/[AMP] ratios stimulate PFK enzyme activity, the product of which (Fructose 1,6-biphosphate) stimulates Pyruvate kinase activity. Remember that Frucose 1,6 bisphophate is an important regulator of Pyruvate kinase! [Berg 2012, Fig. 16.18]

In the pathway Glucose → F-6P →(PFK) → F-1,6BP, PFK is activated by F-2,6-BP. [Not clear? Study the text and figure in Berg 2012, Fig. 16.19 pp. 475–476]

Liver cells and pancreatic cells possess a specialized isozyme of hexokinase, called glucokinase, which is not inhibited by G-6P. Its affinity with glucose is ~ 50 times lower than hexokinase. This makes these cell sensitive to increasing [ATP].

## Citric acid cycle

Acetyl Coenzyme A (CoA) enters the citric acid cycle, where it produces 2CO₂ and 8e¯. But first, pyruvate has to be transformed into acetyl CoA, which also produces 2e¯ and 1CO₂. The pyruvate that is not transformed into Acetyl CoA is transformed into acetate. We don’t have to know exactly how Acetyl CoA is produced from Pyruvate. 🙂

Cells always try to keep a steady state of concentrations of all metabolites.

[Fig 17.1b] Glycolysis occurs in the cytosol. Citric acid cycle happens witin the mitochondrial matrix.

[Fig. 17.19]
A typical exam question would probe if we understand the following: Acetyl CoA is the end product of the fat catabolism pathway. In the citric acid cycle, only 2C from the Acetyl CoA molecule is used to form a CO₂ molecule. Oxalo-acetate cannot be produced from Acetyl CoA. We (and other mammels) cannot produce glucose from fatty acids. The evolutionary reasons for this are unknown.

[Fig. 18.1]
The 8 e-, which are produced, are used to pumpt H+ out of the membrane to create a proton gradient. In this process, O2 is reduced to H20. These protons can only re-enter the membrane through ATP syntase. This process can be disrupted by making the membrane permeable by protons, which leads to overheating. One such compound is present in XTC. A silver bullet drugs would be able to selectively affect permeability of the membrane.

[Fig. 18.17]
Complex I pumps protons. Complex II passes the electrons, via the Q pool, to complex III, which also pumps protons. In the last complex, complex IV, oxygen is reduced to H2O. This energy of reduction (-200 KJ mol-1) is the energy that is transformed in the proton gradient.

[Fig. 18.31]
[Fig. 18.33]
ATP synthase is een ‘mill’ which makes a turn in response to every invading proton. Electron-transport chain pumps protons into the intermembrane space, from which they enter the matrix through ATP synthase, by which ATP is produced from ADP + Pi.

Apparently, protons do leak back through the mitochondrial membranes, which is why oxygen is always used, and metabolic heat is always produced, keeping us warm. To increase warmth production, enzymes exist to increase membrane permeability. Brown fat contains decoupling protein, which does exactly that. If we could entice white fat cells to produce mitochondria, a wonder weight-loss drug could be developed.

## Recapitulation of important principles

• Nutrient uptake is very efficient in humans.
• BMR is an important parameter in energy balance.
• Storage of carbohydrates in the form of glycogen is minor compared to triglycerides and protein.
• The glycolytic/gluconeogenic pathway plays a central role in intracellular metabolism.
• Switch from glycolysis to gluconeogenesis is regulated in part by energy demand. Fructose 2,6-biphosphate is crucial in regulation.
• Acetyl-CoA plays a central role in energy metabolism, but can not be used to synthesize glucose.
• Mitochondrial oxidative phosphorylation is fuelled by NADH/FADH2 derived mostly from citric acid cycle activity.
• The respiratory chains consists of 5 protein complexes.
• ATP synthesis is driven by a proton gradient.

The above is not really a coherent summary of the lecture, but I hope to update it with the help of the textbook to condense it to something briefer that is also more explanatory. 😕

[1] GF Cahill jr, “Starvation in man,” Clinics in endocrinology and metabolism, vol. 5, iss. 2, pp. 397-415, 1976.
[Bibtex]
@article{cahill1976,
title={Starvation in man},
author={{GF Cahill jr}},
journal={Clinics in endocrinology and metabolism},
volume={5},
number={2},
pages={397--415},
year={1976},
publisher={Elsevier}
}