Low phosphorus status might contribute to the onset of obesity

Abstract

Overweight and obesity are becoming global health problems. Although genetics certainly plays a role, weight gain is ultimately the result of a failure in the balance between energy expenditure and energy intake. Obesity during the past few decades was paralleled with several changes in dietary habits favouring low phosphorus consumption. This is believed to compromise adenosine triphosphate (ATP) production that is involved in the regulation of energy metabolism. Ingestion of high‐carbohydrate–low phosphorus food is known to increase insulin release, to simultaneously stimulate peripheral uptake of phosphorus and the phosphorylation of many compounds. This creates a competition for phosphorus that compromises its availability for ATP production, possibly translated into low diet‐induced thermogenesis. Moreover, reduced hepatic ATP production is believed to be transmitted through neural afferents to the central nervous system, resulting in an increase in food intake. On the other hand, the positive relation between phosphorus and red blood cell 2,3‐diphosphoglycerate, which reduces oxygen affinity to haemoglobin, would be expected to reduce the capacity for physical activity. In line with that, plasma phosphorus status was reported to be inversely related to body weight. Adequate intakes of phosphorus are thus potentially protective against rising obesity epidemic across the globe.

Full text

Etiology and Pathophysiology
Low phosphorus status might contribute to the onset
of obesity
O. A. Obeid
Department of Nutrition and Food Science,
Faculty of Agricultural and Food Sciences,
American University of Beirut. Beirut, Lebanon
Received 15 January 2013; revised 8 March
2013; accepted 22 March 2013
Address for correspondence: Professor OA
Obeid, Department of Nutrition and Food
Science, Faculty of Agricultural and Food
Sciences, American University of Beirut,
Beirut 1107 2020, PO Box 11-0236, Lebanon.
E-mail: omar.obeid@aub.edu.lb
Summary
Overweight and obesity are becoming global health problems. Although genetics
certainly plays a role, weight gain is ultimately the result of a failure in the balance
between energy expenditure and energy intake. Obesity during the past few
decades was paralleled with several changes in dietary habits favouring low
phosphorus consumption. This is believed to compromise adenosine triphosphate
(ATP) production that is involved in the regulation of energy metabolism. Inges-
tion of high-carbohydrate–low phosphorus food is known to increase insulin
release, to simultaneously stimulate peripheral uptake of phosphorus and the
phosphorylation of many compounds. This creates a competition for phosphorus
that compromises its availability for ATP production, possibly translated into
low diet-induced thermogenesis. Moreover, reduced hepatic ATP production is
believed to be transmitted through neural afferents to the central nervous system,
resulting in an increase in food intake. On the other hand, the positive relation
between phosphorus and red blood cell 2,3-diphosphoglycerate, which reduces
oxygen affinity to haemoglobin, would be expected to reduce the capacity for
physical activity. In line with that, plasma phosphorus status was reported to be
inversely related to body weight. Adequate intakes of phosphorus are thus poten-
tially protective against rising obesity epidemic across the globe.
Keywords: ATP, obesity, phosphorus.
obesity reviews (2013) 14, 659–664
Introduction
Obesity and increased body adiposity are rapidly emerging
global health problems (1–4). While genetics certainly plays
a role, weight gain is ultimately the result of a failure to
balance energy expenditure and energy intake (food
intake). Overweight and obesity are spread in both high-
and low-income countries and are associated with urbani-
zation and westernization of diets, especially among low-
income urban groups (2). The increases in obesity during
the past few decades have paralleled modernization (indus-
trialization, globalization of food markets, etc.) and several
changes in dietary habits. These are mainly related to the
dramatic increase in the consumption of refined cereals
(where refinement reduces phosphorus content by about
70%) and oils, sugars, and sweeteners such as high fructose
corn syrup (HFCS) which contain negligible amounts of
phosphorus (1–4). These commodities contribute to more
than 50% of the food supply (kcal/capita/day) in most
countries (5), not including the contribution of starchy
foods (e.g. potatoes) that are also low in phosphorus. The
contribution of low phosphorus commodities to total
energy intake is known to be inversely related to income,
especially among urban populations (2). On the other
hand, phosphorus content of major raw (non-refined)
foods (e.g. cereals, pulses, meat) is around 1 mg P/kcal. It
can be predicted that a person consuming a diet of mainly
raw, unprocessed foods with a 2,500 kcal daily energy
obesity reviews doi: 10.1111/obr.12039
659© 2013 The Author
obesity reviews © 2013 International Association for the Study of Obesity 14, 659–664, August 2013

intake would consume about 2.5 g of phosphorus, which is
lower than the 4 g d-1upper limit of intake (6). Such a diet
is believed to have been consumed by our ancestors before
the industrial advancement. Current daily phosphorus
intake is about 1.4 g d-1(7), although concern has been
raised regarding the contribution of phosphorus containing
additives, cola beverages (~16 mg/100 mL), etc., as well as
the bioavailability of phosphorus from different sources
(8). This intake is lower than the predicted intake when
consuming a diet with 1 mg P/kcal, but is above the present
recommended daily allowance (RDA) of 700 mg. It should
be mentioned that RDA is based on the lower end of the
normal adult serum inorganic phosphate (Pi) and that this
would have been 2,100 mg if it had been based on the
middle of the normal range (6). On the other hand, food
habits are known to vary according to socioeconomic
status, with high energy dense-nutrient poor foods highly
consumed by people of low socioeconomic status, mainly
because of their high energy density (kcal g-1food) and
low energy cost ($US0.1–$US1/1,000 kcal) (1–4,9). Such
dietary habits were proposed to be one factor behind the
high prevalence of obesity among people of low socioeco-
nomic status (9), and this may implicate phosphorus in this
process due to the fact that these foods are known to be low
in phosphorus. Thus, given the increased prevalence of
obesity among people consuming high quantities of food
containing low levels of phosphorus, it is reasonable to
postulate that low phosphorus intake may be involved in
the development of obesity.
Phosphorus, adenosine triphosphate and
energy balance
The production of adenosine triphosphate (ATP), including
hepatic ATP, depends upon adequate sources of phospho-
rus (P) (10,11), and this is coupled with two other factors.
First, only limited quantities of free phosphate are stored
within cells, and most tissues depend upon extracellular
fluid (ECF) Pifor their metabolic phosphate, and under low
ECF Pilevels, cellular dysfunction follows. Second, there is
virtually constant fractional phosphorus absorption across
a broad range of intakes (6), suggesting a lack of an adap-
tive mechanism that improves phosphorus absorption at
low intakes, as can occur with some other micronutrients.
Therefore, phosphorus availability in food becomes an
important factor that governs phosphorus levels in the
circulation and in turn its availability for ATP production.
Thus, low phosphorus intake would be expected to reduce
ATP production, which is believed to affect food intake and
energy expenditure.
The physiological regulation of food intake, which acts
principally at the central level, is believed to be partially
governed by signals originating from the liver via the
hepatic postprandial metabolism involving ATP production
(12,13). Evidence supports a relationship between declin-
ing hepatic ATP levels and increasing food intake; this
decline is thought to transduce changes in hepatic energy
status into neural signals or hepatic vagal afferent activity
that is transmitted to the central nervous system (12–17).
Moreover, there are controversial data on the difference in
diet-induced thermogenesis (DIT) between lean and obese
subjects (18–23), with a large number of studies showing
reduced DIT in obesity (19–23), that seems to be normal-
ized upon losing weight (22,23), indicating that DIT is not
a causal factor for obesity. However, reduced DIT of dia-
betic as compared to non-diabetic obese subjects (24) may
implicate insulin in this process (25). The reduction in DIT
of obese diabetic subjects, with both increased and reduced
insulin response (24), implies that this reduction is not
related to insulin per se, but rather to its function. Insulin
resistance is known to be inversely related to peripheral
uptake of glucose (impaired glucose tolerance) and phos-
phorus, implicating the latter in this process, especially that
peripheral uptake is known to be reduced with the progres-
sion of insulin resistance to impaired glucose tolerance and
diabetes (26).
In addition, plasma phosphorus is known to be posi-
tively related to red blood cell (RBC) ATP and 2,3 diphos-
phoglycerate (2,3-DPG) concentration, which is known
to decrease the oxygen affinity to haemoglobin (27–31).
Reduced 2,3-DPG would be expected to decrease oxygen
availability for oxidation, which in turn would contribute
to lowering the capacity for physical activity resulting in a
reduction in energy expenditure.
Thus, it is the hypothesis that low phosphorus status may
contribute to the development of obesity through its role in
the regulation of food intake, thermogenesis and capacity
for physical activity. (Fig. 1).
Dietary habits, phosphorus and body weight
Several dietary factors are known to compromise phospho-
rus availability for ATP production. Ingestion of a high
carbohydrate-low phosphorus meal is known to induce a
marked reduction in plasma Pistatus (32–34) mainly due to
the stimulation of insulin release, which is known to
increase phosphorus uptake by peripheral tissues (mainly
muscles) (35) and phosphorylation of many compounds
(e.g. protein, carbohydrate, etc.). This creates competition
for phosphorus between ATP production and the phospho-
rylation of other compounds.
Fructose is known to have a ‘phosphate-sequestering’
capacity, where fructose 1-phosphate accumulates in the
liver because, unlike for glucose, there is no feedback
mechanism for fructose phosphorylation. This makes
phosphorus unavailable to participate in other essential
metabolic reactions, including the regeneration of ATP
(10,15,36,37). Therefore, under high fructose or high
660 Phosphorus and obesity O. A. Obeid obesity reviews
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obesity reviews © 2013 International Association for the Study of Obesity14, 659–664, August 2013

glucose/low phosphorus conditions, competition for phos-
phorus occurs between ATP production and phosphoryla-
tion of other compounds.
Studies looking at the relation between phosphorus
intake and body weight have reported conflicting findings
(38,39). While those looking at serum phosphate were
consistently reported to be inversely related to body weight
(40–49) (Table 1), hypophosphatemia was proposed to be
involved in the development of the metabolic syndrome,
including increased body mass index (BMI) (50). The simi-
larity in phosphate fractional excretion rate between lean,
overweight and obese subjects implied that the reduction in
serum phosphate was mainly attributed to a reduction in
dietary intake rather than to problems with excretion (42).
It is therefore possible to suggest that phosphorus is
involved in the regulation of body weight.
Many studies are in support of a role for phosphorus or
hepatic ATP in the regulation of body weight and food
intake. Several abnormalities in hepatic ATP were reported
in animal and human experiments on obesity (50–52). In
humans, liver ATP status was reported to be affected by
fructose consumption (53) and infusion (51). In addition,
hepatic ATP stores (52) and recovery from hepatic ATP
depletion (using fructose infusion) (51) were inversely
related to BMI. Moreover, an analysis of metabolic data
using the Knowledge Discovery in Databases concluded
that ATP deficiency or decreased energy levels were
strongly linked to the development and sustenance of
obesity by driving overeating and conserving energy (54).
Thus, human studies indirectly support a potential role for
hepatic ATP in energy and body weight regulations (52,53).
In line with that, we have recently found that the addition
of 500 mg P to different carbohydrate preloads caused a
substantial reduction in ad libitum subsequent energy
intake (27–33%) (55).
There is also evidence in support of phosphorus involve-
ment in thermogenesis. Addition of phosphorus to orange
juice was reported to increase postprandial thermogenesis
of obese but not lean subjects (56,57), and phosphorus
supplementation of obese subjects, in a weight reducing
program, was shown to increase resting metabolic rate
(58,59). It is thus believed that phosphorus supplementa-
tion may have exerted its effect through an increase in
peripheral phosphorus (as well as glucose) uptake, espe-
cially that P is known to stimulate insulin sensitivity
(26,40,60). Pointing to the capacity of P for inducing
physical activity, there are limited and inconsistent data on
RBC 2,3-DPG concentration of obese subjects (57,61,62).
Nevertheless, the magnitude of increase in RBC 2,3-DPG
concentration following phosphate loading (27,30,57) was
reported to be higher in obese as compared to lean subjects,
and this was accompanied with higher energy expenditure
in the former (57). Along the same lines, obesity was
reported to be associated with chronic fatigue syndrome
(63) and physical fatigue (64), and phosphate loading (up
to4gd
-1) has been used for different durations to improve
physical performance (65).
Discussion
Phosphorus may provide a link between different observa-
tions associated with increased body weight or energy
intake. The phosphate-sequestering capacity of fructose
may be involved in the synergetic relation between HFCS
intake and obesity (66). The high phosphorus content of
protein may be implicated in the reduction of energy intake
under conditions of increased protein intake (67,68), as
well as in the decrease in body weight and fat mass under
an isocalorically high-protein diet (69). In addition, the
high phosphorus content of milk may partially explain the
inverse association between dairy product intake and body
weight, especially given that calcium failed to clarify such
an association (70–72). In fact, increased calcium intake
from both diet and supplements is known to reduce phos-
phorus absorption (73), and calcium carbonate in high
doses is used as phosphate binder. Moreover, the inverse
relationship between increased intake of whole grains and
the risk of the different components of metabolic syndrome
(74,75) may be partially explained by their richness in
phosphorus, as added cereal fibre failed to induce such an
Hyperphagia
High CHO-Low P
High Insulin release
Increased P uptake and phosphorylation
Liver Muscle
Low hepatic ATP production Low ATP production
Low thermogenesis
Increased efficiency of weight gain
Competition for phosphorus
Weight gain Obesity
Figure 1 Proposed interaction among phosphorus, adenosine
triphosphate (ATP) production and obesity.
obesity reviews Phosphorus and obesity O. A. Obeid 661
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obesity reviews © 2013 International Association for the Study of Obesity 14, 659–664, August 2013

effect and was proposed to be a marker of other compo-
nents of whole grains that impart health advantages (76).
On the other hand, the ability of phosphate depletion to
simulate glucose intolerance, probably through the stimu-
lation of hepatic glucose production and reduced insulin
level (77) that requires ATP for its release by pancreatic
b-cells (78), is supported by several observations. For
example, increased serum phosphate and phosphorus
intake of non-diabetic subjects were reported to be syner-
gistically related to improvement in glucose tolerance
(32,40) and insulin sensitivity (26,32,40,47,60). Thus,
reduced phosphorus status would favour the development
of obesity, as postprandial glycaemia is known to be impli-
cated in the development of chronic metabolic diseases
such as obesity, type 2 diabetes mellitus and cardiovascular
disease (79). Such a process can be further aggravated
by the development of obesity that is characterized by
insulin resistance, which predisposes to the development
of impaired glucose tolerance that is known to decrease
peripheral uptake of both glucose and phosphorus (26),
therefore reducing the capacity of ATP synthesis that would
be translated into a reduction in thermogenesis (26,80).
In summary, ATP production, which is dependent on
phosphorus availability, is essential for many processes
including eating behaviour and energy expenditure.
Increased consumption of refined cereals, potatoes, sugars
(fructose) and oils, which are characteristics of the modern
diet, would negatively impact phosphorus availability.
Insulin release stimulates the phosphorylation of many
compounds and this may compromise phosphorus avail-
ability for ATP production, especially given that ATP seems
to act as a phosphate donor (37). Thus, increased insulin
release under low phosphorus diet exacerbates the situa-
tion. Moreover, reduced phosphorus peripheral uptake due
to impaired glucose tolerance was postulated to affect ther-
mogenesis (26,80). It is also reasonable to postulate that
boosting the status of phosphorus in food would amelio-
rate such metabolic changes. This can be accomplished by
fortification (e.g. white flour) and/or the establishment of a
carbohydrate to phosphorus ratio comparable to that of
carbohydrate to thiamine or energy to thiamine.
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obesity reviews © 2013 International Association for the Study of Obesity14, 659–664, August 2013