Metabolism during Fasting and Starvation: Understanding the Basics to Glimpse New Boundaries

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Metabolism during Fasting and Starvation: Understanding the Basics to
Glimpse New Boundaries
Moacir Couto de Andrade Júnior1,2*
1Post-Graduation Department, Nilton Lins University, Manaus, Brazil
2Department of Food Technology, Instituto Nacional de Pesquisas da Amazônia (INPA), Manaus, Brazil
*Corresponding author: Andrade Jr MC, Department of Food Technology, Instituto Nacional de Pesquisas da Amazônia (INPA), Manaus, Brazil, Tel: +55 (92)
3633-8028; E-mail: moacircoutjr@gmail.com
Received date: Sep 19, 2017; Accepted date: Sep 25, 2017; Published date: Sep 28, 2017
Copyright: © 2017 Andrade Jr MC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Editorial
e human diet is a complex mixture of interacting components
that cumulatively aect health [1]. e metabolizable energy of
macronutrients (i.e., carbohydrates, proteins, and lipids) is responsible
for the bulk of the energy in the human diet. Micronutrients (i.e.,
minerals and vitamins) play a central role in metabolism and in the
maintenance of tissue function [2]. Metabolism encompasses all of the
biochemical processes used by organisms to synthesize structural and
functional constituents and to obtain energy. It is typically divided into
anabolism, which includes the biosynthesis of macromolecules such as
glycogen, proteins, and lipids (e.g., triacylglycerol, TAG) and
catabolism, which includes the degradation of macromolecules into
their simplest precursors: glucose, amino acids, glycerol, and fatty
acids. e free energy released by catabolic degradation- via adenosine
triphosphate and nicotinamide adenine diphosphate- is used to drive
the endergonic processes of anabolic biosynthesis [3]. Carbohydrates
(e.g., glycogen) constitute immediate energy stores (liver), and lipids
(e.g., TAG) constitute long-term energy stocks (adipocytes) [4].
Proteins constitute the active (functional) cell mass and are a minor
source of energy [4].
Pancreatic insulin and pituitary growth hormone (GH)- via the
hepatic eector insulin-like growth factor-1 (IGF-1)- are examples of
anabolic hormones. Gastric ghrelin is another anabolic hormone that
stimulates appetite, other endocrine secretions (pituitary GH,
prolactin, and adrenocorticotropic hormone), and weight gain [5].
Androgens (e.g., testosterone) may have an anabolic eect (protein
synthesis) [6]. Anabolism increases the requirements for all nutrients,
including micronutrients, that should be supplied when patients are
gaining weight [2]. On the other hand, pancreatic glucagon and
adrenal epinephrine and cortisol are examples of catabolic
(hyperglycemic) hormones. ese hormones, together with GH,
counter-regulate hypoglycemia (i.e., a plasma glucose less than 70 mg/
dL). Pancreatic glucagon, in particular, stimulates the liver to release
glucose via glycogenolysis (i.e., the breakdown of glycogen) and
gluconeogenesis (i.e., glucose synthesis from non-glycosidic substrates)
and stimulates adipose tissue to release free fatty acids (FFAs) and
glycerol via lipolysis (i.e., the breakdown of TAG) [3]. yroid
hormones (e.g., triiodothyronine or T3) are catabolic and play an
important role over the long term in determining the set of
metabolism [6]. Adipocyte leptin is catabolic in nature and inhibits
food intake and lipid storage while promoting energy expenditure [7].
e catabolism associated with acute injury (e.g., infection, surgery, or
trauma) leads to elevated energy expenditure and protein breakdown,
increasing the requirements for vitamins and minerals [2,8]. At this
phase, anabolism is postponed in favor of catabolism [8].
ere is also amphibolic metabolism, so-called for serving both
anabolic as well as catabolic pathways. e enzymes (and their
substrates) of this bi-directional metabolism remain better studied in
prokaryotic organisms (bacteria) such as
Escherichia coli
, whose
teleonomy of certain strains enables metabolic versatility that is mainly
linked to the citric acid cycle, also known as tricarboxylic acid or the
Krebs cycle [9]. Other dynamic aspects of this vital metabolic cycle
include anaplerosis and cataplerosis; the rst term refers to the relling
of the Krebs cycle whenever an intermediate leaves the mitochondria
during biosynthetic events, and the second term refers to the opposite
function (i.e., the removal of accumulating citric acid cycle anions)
[10].
e fact that metabolism occurs in many stages mediated by
numerous enzyme substrates and products (metabolites) motivates the
term intermediate metabolism. e metabolism of macronutrients is
particularly interrelated [4]. For instance, glucose may be synthesized
from lactate, glycerol, and amino acids (e.g., alanine)
(gluconeogenesis), but not from fatty acids [4]. In contrast, the
dihydroxyacetone phosphate used to make glycerol-3-phosphate (G3P)
for TAG synthesis derives either from glucose via the glycolytic
pathway (or Embden-Meyerhof pathway) or from oxaloacetate via an
abbreviated version of gluconeogenesis termed glyceroneogenesis [3].
Importantly, both gluconeogenesis and glyceroneogenesis are
cataplerotic pathways because they convert citric acid cycle anions to
phosphoenolpyruvate, which is then used to make either glucose or
G3P [10].
It should be emphasized that glucose and FFAs are the most
important energy substrates for most organisms (including humans)
and that intermediate metabolism reects the primacy of these fuels.
Moreover, the existence of metabolic cycles such as glucose-lactate (the
Cori cycle), glucose-fatty acid (the Randle cycle), and glucose-alanine
(the Cahill cycle) reinforces this idea.
Each day, a human’s three primary meals are breakfast, lunch, and
dinner, which are interspersed by interprandial fasting periods of
approximately ve hours each. e longest fasting period corresponds
to nocturnal fasting (roughly eight hours). Sleep eectively imposes an
extended period of fasting during which energy metabolism diers
between sleep stages and begins to increase prior to awakening [11].
Fasting metabolism is clearly adapted to ensuring the orderly
mobilization of endogenous substrates and energy for maintaining
vital activity [12]. It is characterized by low insulin levels, high
glucagon levels, liver glycogenolysis, and gluconeogenesis for
maintaining serum glucose levels and cerebral function [13,14].
Fasting metabolism also involves high levels of lipolysis and FFAs via
circulating TAG for enabling energy utilization by most tissues other
than the brain and the central nervous system (CNS) [13,14]. Glucose
Journal of Nutrition and Dietetics
Andrade Jr, J Nutr Diet 2017, 1:1
Editorial OMICS International
J Nutr Diet, an open access journal Volume 1 • Issue 1 • e02

then reaches the CNS through specic transporters (e.g., GLUT1 and
3) [15]. As fasting continues, progressive ketosis develops due to the
mobilization and β-oxidation of fatty acids and the increase in ketone
bodies (KBs) (e.g., β-hydroxybutyrate) that replace glucose as the
primary energy source in the CNS, thereby decreasing the need for
gluconeogenesis and sparing protein catabolism [3,16]. At this stage,
hormonal adaptive changes involve, for example, low insulin and T3
levels along with high levels of ketogenic glucagon and the inactive
metabolite of T3 (i.e., reverse T3 or rT3) [16]. Ketone bodies reach the
CNS via monocarboxylic acid transporters (e.g., MCT1 and 2) [15].
e brain and other organs utilize KBs in a process termed ketolysis
[17]. On the contrary, in the fed state, postprandial metabolism is
essentially characterized by high insulin levels responsible for both
antilipolytic and antigluconeogenic actions (by suppressing these two
pathways) and lipogenic actions (e.g., by stimulating the enzyme
lipoprotein lipase (EC 3.1.1.34), which hydrolyzes the TAG of
chylomicrons and very low-density lipoprotein at the endothelial
surface, which releases FFAs and glycerol for adipocyte storage)
[13,14,18]. Aquaglyceroporins (e.g., AQP7 and 9) are responsible for
transporting glycerol in the adipocytes [19]. erefore, insulin plays an
essential role in controlling energy metabolism in both a fasting state
(in which it prevents severe ketoacidosis) and also in a fed state (in
which it promotes fuel storage) [14,20]. Diabetic patients, especially
type 1 diabetics, may develop severe ketoacidosis due to a profound
insulin deciency [14].
Fasting oen refers to abstinence from food, and the term starvation
is used to describe a state of extreme hunger resulting from a
prolonged lack of essential nutrients [21]. Hence, the adaptive fasting
briey described above is an evolutionary tactic distinct from
starvation [22]. Starvation is, in principle, longer, potentially harmful,
and may lead to a lethal outcome. Additionally, fasting and starvation
are not synonymous terms, but the expression prolonged fasting is
used as a synonym to starvation in the literature. e response to
starvation is integrated at all levels of organization and is directed
toward the survival of the species [21]. Hunger is an adaptive response
to food deprivation that involves sensory, cognitive, and
neuroendocrine changes (e.g., increased neuropeptide Y or NPY) that
motivate and enable food-seeking behavior [17]. As carbohydrate
reserves are rapidly depleted, and protein sources are minor, the
survival period of starving individuals depends more on fat reserves
than on muscle mass (e.g., obese individuals can survive for several
months without eating in clinically supervised weight-reduction
programs) [3,4,16]. Apart from the rapidly depleted hepatic
glycogenolysis, the other major metabolic pathways of energy supply
supplement one other during prolonged fasting or starvation (Figure
1). e increased serum rT3 and the decreased T3 lead to conservation
of energy and a decrease in protein breakdown [23]. e increase in
renal gluconeogenesis is accompanied by an augmentation in
ammonia formation, as evidenced by the increased urinary excretion
of ammonia [14,20]. Nevertheless, adipocyte lipolysis (with weight
loss) for liver ketogenesis becomes the most prominent interrelated
metabolic pathway during starvation [14,20]. If starvation continues
until the adipose stores are depleted, muscle is rapidly degraded for
gluconeogenesis, potentially leading to a lethal outcome [14,20,22].
Figure 1: Simplied overview of the hormonal and metabolic
alterations during food deprivation. Note: ↓, low; ↑, high; CATs,
catecholamines (epinephrine and norepinephrine). Plasma CATs
are unchanged aer 36 hours of fasting, but they are signicantly
increased aer 72 hours of fasting [24]. Glucose-6-phosphatase (EC
3.1.3.9) is an enzyme found mainly in the liver and the kidneys [25].
It plays the important role of providing glucose during starvation
[14,25].
It is possible to glimpse the new boundaries to which the
metabolism of starvation has been placed. Critical illness represents a
multifarious cellular insult with damage induced by hypoxia,
hypoperfusion, and inammation, and the removal of cell damage by
autophagy is essential for recovery [26]. Autophagy is an evolutionarily
conserved process that degrades cellular components to restore energy
homeostasis under limited nutrient conditions such as starvation [27].
us, starvation promotes autophagy [28]. On the contrary,
suppressive eects by nutrients early during critical illness could
compromise such damage removal systems [26]. How this starvation-
induced autophagy is regulated at the whole-body level is not entirely
understood yet [27]. However, anabolic hormones (e.g., insulin and
IGF-1) and catabolic hormones (e.g., glucagon and CATs) are
signicant regulators of autophagy [29].
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e02.
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