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THE HORMONAL CROSSTALKS WITHIN SANTORIO 
ON HIS WEIGHING CHAIR
Nina MOHORKO
University of Primorska, Science and Research Centre of Koper, Institute 
for Kinesiology Research, Garibaldijeva 1, 6000 Koper, Slovenia
e-mail: nina.mohorko@zrs.upr.si
ABSTRACT
Santorio Santorio studied metabolism by spending decades seated on a weighing 
chair, studying the influences of changes in body weight on human health and well-
being. Today, metabolism research is oriented toward the hormonal crosstalks which 
regulate plasma glucose levels, the amount of fat deposits in adipose tissue and feeding. 
In the search for brain acting metabolism controlling factors, endocrine function has 
been observed in organs previously not thought of as endocrine organs, such as the 
stomach and white adipose tissue. The stomach is the main ghrelin secreting organ, 
while white adipose tissue is the main leptin secreting organ. These two opposing hor-
mones act on the hypothalamus to regulate energy homeostasis – ghrelin in the case of 
negative energy balance and leptin in the case of the increased amount of fat deposits 
in adipose tissue. The two hormones display a circadian pattern in their secretion. In 
fact, the regulation of metabolism is controlled by the circadian clock, but the circadian 
clock itself is also strongly influenced by food intake.
Keywords: ghrelin, leptin, energy homeostasis, circadian clock
Review article                   UDC: 612.06:616.8
Received:
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POGOVORI HORMONOV V SANTORIJU NA STOLU-TEHTNICI
IZVLEČEK
Santorio Santorio je preučeval metabolizem tako, da je desetletja preživel na stolu-
tehtnici in opazoval vplive sprememb telesne teže na človekovo zdravje in počutje. 
Danes je raziskovanje metabolizma usmerjeno k navzkrižnim govorom hormonov, ki 
nadzorujejo nivo glukoze v plazmi, količino maščob v maščevju in prehranjevanje. V 
iskanju faktorjev, ki nadzorujejo metabolizem in delujejo na možgane, so odkrili endo-
krino funkcijo v organih, ki jim je prej niso pripisovali, kot sta želodec in belo maščevje. 
Želodec je glavni organ, ki izloča grelin, belo maščevje pa glavni organ, ki izloča 
leptin. Ta nasprotujoča si hormona pri nadzoru energijske homeostaze delujeta na 
hipotalamus – grelin, ko je energijska bilanca negativna, leptin pa, ko se nivo maščobnih 
odlag v maščevju poveča. Izločanje obeh hormonov ima cirkadiani vzorec. Nasploh je 
metabolizem nadzorovan s cirkadiano uro, toda tudi sam vnos hranil ima močan vpliv 
na cirkadiano uro. 
Ključne besede: grelin, leptin, energijska homeostaza, cirkadiana ura
INTRODUCTION
”If there daily be an Addition of what is wanting, and a Substraction of what abonds, 
in due Quantity and Quality, lost Health may be restor’d, and the present preserv’d.” 
wrote Santorio Santorio about the importance of balance in food consumption in his 
first aphorism (Santorio, Keill & Quincy, 1720). Santorio spent decades seated on a 
weighing chair (Figure 1), studying the influence of changes in body weight on hu-
man health and well-being. He gathered his observations in his book of aphorisms De 
Statica Medicina, first published in 1614, emphasizing the importance of maintaining 
a constant weight in the first section of the book. The second edition of De Statica Me-
dicina (1615) was reprinted many times (around 40) and was translated into English 
(1676), Italian (1704), French (1722) and German (1736) (Kuriyama, 2008). Santorio 
was one of the most important medical doctors in Europe in his time, and was still 
widely read over a century after his death (Kuriyama, 2008).
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Four hundred fifty years after Santorio’s birth, the control of body weight is still a 
subject of scientific research. Scientists have moved away from the use of a weighing 
chair to measure fluctuations in body weight to research focussed on what happens in-
side the body: trying to unravel the complicated nature of controlling body weight which 
has proven to be the sum of multiple metabolic processes, such as whole body energy 
expenditure, body temperature, locomotor activity, cardio-respiratory parameters and 
lipogenesis (Gautron & Elmquist, 2011). The metabolic balance is measured in plasma 
levels of crosstalking hormones and cytokines which are excreted from various tissues 
and which determine the fate of energy substrates. However, the idea of weighing the 
food one eats and balancing it with energy consumption has never been so advertised 
and written about in popular media. An abundance of energy rich food on one side of the 
scale and a sedentary lifestyle on the other make the import of calories into the daily diet 
Figure 1: Santorio Santorio on a weighing chair. Frontispiece of De Statica Medicina. 
From Santorio, S., Keill, J., Quincy, J. (1720). Medicina Statica: being the aphorisms 
of Sanctorius, translated into English, with large explanations. To which is added Dr. 
Keil’s Medicina Statica Britannica, with comparative remarks and explanations. As also 
medico-physical essays on [...] by John Quincy. Second edition. London: Printed for W. 
and J. Newton in Little-Britain, digitized by Google from the library of Oxford University.
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far higher than the energy expenditure from physical activity. This has led to the obesity 
epidemic which is of major concern to the World Health Organization since overweight 
and obesity are the fifth leading risk for death worldwide (WHO, 2011). Furthermore, 
behavioural sleep deprivation and the disruption of sleep and feeding patterns are found 
to be alarmingly on the increase within the population, adding to the enhanced life-style-
connected all cause morbidity (AlDabal & BaHammam, 2011). This brief paper intro-
duces the complicated network of hormones responsible for the maintenance of body 
weight. The maintenance of constant of body weight was observed as a characteristic 
of a healthy person by Santorio Santorio over four centuries ago (Santorio et al., 1720).
Hormonal crosstalk and energy control
The maintenance of a constant body weight is made possible by the regulation of 
food intake which is a result of a conversation of all the tissues involved in energy 
metabolism – namely the intestine, pancreas, liver, adipose tissue, muscle and central 
nervous system through hormonal and neural pathways. While discovering the bio-
chemical fine-tuning of energy homeostasis, endocrine function has been attributed to 
organs not traditionally thought of as endocrine organs. The interdependence of regu-
lating molecules is especially evident in cases of a disrupted metabolic state, such as in 
insulin insensitivity and in imbalance in blood glucose levels.
In response to fasting (Asakawa et al., 2001), the stomach secretes a hormone known 
as ghrelin (Kojima et al., 1999). Ghrelin is a strong appetite inducer (Asakawa et al, 2001; 
Wren et al., 200l) which promotes increased food intake (Wren et al., 200l). Human plas-
ma ghrelin concentrations fluctuate over the course of the day in relation to food intake 
(Williams & Cummings, 2005). Ghrelin communicates with the brain through neural af-
ferents from the periphery – the vagus – or by direct action (LeSauter, Hoque, Weintraub, 
Pfaff & Silver, 2009). Ghrelin receptors (GHS-R) are distributed in the hypothalamus – 
especially in the arcuate nucleus which also responds to other feeding-control hormones 
– but also in other brain structures involved in feeding control (Guan et al., 1997). The 
injection of ghrelin into the fourth ventricle of rats had a hyperphagic effect through brain-
stem GHS-R, reducing the interval between meals (Faulconbridge, Cummings, Kaplan 
& Grill, 2003). In the ventral tagmental area, ghrelin has a strong effect on dopaminergic 
neurons, thus also regulating feeding through the mesolymbic reward system (Abizaid et 
al., 2006). Outside the nervous system, ghrelin receptor was found in wide range of tissues 
such as the myocardium, adrenal gland, skeletal muscle, adipose tissue and others (Papotti 
et al., 2000). Ghrelin administration in humans increased the motility of the proximal gas-
trointestinal tract (Tack et al., 2006). Recent evidence suggests ghrelin’s primary role in 
energy metabolism during negative energy balance and starvation – being indispensable 
for blood glucose control during starvation (Briggs & Andews, 2011). Ghrelin potenti-
ates insulin release in the presence of glucose and might function as an anabolic signal 
molecule during energy depletion (Date et al., 2002). Circulating ghrelin concentration is 
reduced in dietary induced obesity as are the ghrelin actions which induce increased food 
intake in the arcuate nucleus of the hypothalamus (Briggs & Andews, 2011). Inactivity 
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during a five week bed rest experiment caused a drop in plasma ghrelin concentration 
and an elevation of insulin concentration, independently of energetic balance (Biolo et al, 
2008). Apart from the orexigenic properties, the influence on gastric motility and glucose 
regulation, ghrelin is reported to have antioxidant and anti-inflammatory properties, thus 
protecting gastric mucosa (Suzuki, Matsuzaki & Hibi, 2011).
In contrast to the orexigenic nature of ghrelin, most food regulating hormones give 
signals about satiety. White adipose tissue (WAT) is not just an energy repository, but also 
an active endocrine and secretory organ (Trayhurn & Beattie, 2001). It secrets adipokines, 
pro-inflammatory cytokines and chemokines such as leptin, adiponectin, resistin, tumor 
necrosis factor α, interleukin (IL) 1β, IL 6 and others (Federico et al., 2010). The adi-
pokines leptin and adiponectin influence glucose and lipid metabolism and energy home-
ostasis (Pedrosa et al., 2011) in an opposing manner to ghrelin. Leptin indicates the size 
of lipid stores in adipose tissue to the hypothalamus (Arch, 2005). Leptin receptors are 
expressed in many nuclei of the hypothalamus – in the arcuate nucleus, leptin suppresses 
the neurones with orexigenic activity (Arch, 2005). The concentration of leptin is higher 
in obese individuals compared to normal weight individuals while the concentration of 
adiponectin is lower in the obese compared to those of normal weight (Valle, Martos, 
Gascón, Cañete, Zafra, & Morales, 2005). Plasma leptin level is significantly increased 
due to inactivity combined with a positive energy balance (Biolo et al., 2008). In obese 
people, along with elevated plasma leptin concentration, leptin resistance is observed 
(Arch, 2005). As the latter is also observed in diet induced obesity, leptin might be rela-
tively ineffective in countering hedonistic feeding or might have a plateau above which it 
is no longer effective (Arch, 2005).
The circadian clock and metabolism
“There are two Kinds of insensible Perspiration, the one is during Sleep, of Humours 
that are well digested, and after which there is an encrease of Strength: the other is when 
awake, and arises from indigested Humours, and is weakening more or less, according to 
the greater or lesser Actions of the Muscles during that Time.” explains Santorio (1720) 
the differences in metabolism between day and night in his Aphorism XX. John Quincy, 
who translated and commented on Santorio’s De Medicina Statica, in his explanation to 
this aphorism states “... during the relaxed State of the Nerves in sleep, that Secretion 
which is made in the Brain, and by which they are supply’d with a convenient Juice neces-
sary for their Invigoration [...] Whereas waking, the Vibrations of Pulsations of the Solids, 
upon which the Motions of the Fluids altogether depend, are more disturb’d and irregular, 
being subject to Alterations from Abundance of Causes, even from the Thoughts that pass 
through the Mind; whereby the Juices are more confused, and the Secretions no so perfect 
[...]” (Aph. XX, Santorio et al., 1720). Santorio and Quincy observed a difference in me-
tabolism due to changes between day and night. Indeed, changes in the ligh-dark cycle are 
physiological cues which control food intake, physical activity and the sleep to wakeful-
ness ratio which leads to the evolution of circadian clocks which reflect the 24 hour day in 
almost all living beings (Gimble, Sutton, Bunnell, Ptitsyn & Floyd, 2011). The circadian 
clocks try to minimise energy consumption and maximise the chance of survival by an-
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ticipating daily-repeating events, and suitably adapt physiology and behaviour to these 
events. The circadian timing system in the suprachiasmatic nucleus of the hypothalamus 
is regulated by light and controls the peripheral circadian clocks. Circadian clock-related 
metabolic regulation in humans is tightly linked to the regulation of sleep (Kovac, Husse 
& Oster, 2009). Increasing evidence suggests that circadian biology could have a signifi-
cant effect on the rising incidence of obesity which coincides with the shortened duration 
of sleep in the general population (Gimble et al., 2011). Both, leptin and ghrelin have 
diurnal oscillations in their expression. Acute shortage of sleep in healthy subjects resulted 
in an increased appetite, reduced leptin secretion, increased ghrelin concentration and 
increased glucose resistance (Spiegel, Tasali, Penev, Van Cauter, 2004). A study on the ef-
fect of CLOCK 3111 T/C polymorphism, which governs sleep duration and morningness/
eveningness on the ability to lose weight showed that CLOCK 3111 C allele carriers who 
had a shorter sleep duration and evening preference also had higher ghrelin levels, showed 
a trend towards overeating and saw reduced weight loss (Garaulet et al., 2011). However, 
the communication between the circadian clock and metabolism is bidirectional: meta-
bolic processes also give feedback to circadian timing (Kovac et al., 2009). Feeding mice 
during the day when they normally sleep inversed the phase of their peripheral circadian 
oscillators (Damiola et al., 2000). The current model of mammalian circadian clocks pro-
poses that they are based on cellular oscillators built from a set of clock genes organised 
in interlocked transcriptional feedback loops (Kovac et al., 2009). An as yet unidentified 
endogenous circadian timing system called food-entrainable oscillators (FEOs) functions 
independently of light to predict the availability of food by activating food-seeking behav-
iour and enabling the synthesis and secretion of enzymes, necessary for digestion before 
regularly timed meals (LeSauter et al., 2009). FEOs secrete hormones which are potential 
regulators of food anticipatory activities and responses that precede food presentation 
(Silver & Balsam, 2010). Ghrelin expressing oxyntic cells in the stomach express clock 
genes and are thought to be one of the FEOs (LeSauter et al., 2009).
CONCLUSION
Energy metabolism is regulated by centrally acting hormones excreted from or-
gans which take part in nutrient processing and energy storing. Ghrelin acts in cases 
of negative energy balance and leptin in cases of an increased amount of fat deposits 
in adipose tissue. The two hormones display a circadian pattern in their secretion. In 
fact, the regulation of metabolism is controlled by the circadian clock, but the circadian 
clock itself is also strongly influenced by food intake – stomach oxyntic cells could be 
possible food-entrainable oscillators.
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