Nutritional Neuroscience, February/April 2006; 9(1/2): 1–10

REVIEW

Relationship between fatty acids and the endocrine and neuroendocrine

system

SAM J. BHATHENA

Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, USDA, Beltsville,
MD, USA, and The George Washington University School of Medicine, Washington, DC, USA

(Received 3 November 2005; revised 9 February 2006; accepted 9 February 2006)

Abstract
Significant interactions exist between fatty acids and the endocrine system. Dietary fatty acids alter both hormone and
neuropeptide concentrations and also their receptors. In addition, hormones affect the metabolism of fatty acids and the fatty
acid composition of tissue lipids. The principal hormones involved in lipid metabolism are insulin, glucagon, catecholamines,
cortisol and growth hormone. The concentrations of these hormones are altered in chronic degenerative conditions such as
diabetes and cardiovascular disease, which in turn leads to alterations in tissue lipids. Lipogenesis and lipolysis, which
modulate fatty acid concentrations in plasma and tissues, are under hormonal control. Neuropeptides are also involved in lipid
metabolism in brain and other tissues. Polyunsaturated fatty acids are also precursors for eicosanoids including
prostaglandins, leucotrienes, and thromboxanes, which have hormone-like activities. Fatty acids in turn affect the endocrine
system. Saturated and trans fatty acids decrease insulin concentration leading to insulin resistance. In contrast,
polyunsaturated fatty acids increase plasma insulin concentration and decrease insulin resistance. In humans, v3
polyunsaturated fatty acids alter the levels of opioid peptides in plasma. Free fatty acids have been reported to inhibit glucagon
release. Fatty acids also affect receptors for hormones and neuropeptides.

Keywords: Fatty acids, fatty acid metabolism, endocrine system, neuroendocrine system, diabetes

Introduction acid endocrine systems are summarized in Table I.

Fatty acids and lipids are an important source of
energy. However, since 1930’s when some fatty acids
were discovered as essential, they have been shown to
play many important roles in biological processes,
either directly or through their modifications. Most of
the processes involved in fatty acid metabolism have
been now shown to be controlled by hormones and
neuropeptides. Thus, several key steps in the
synthesis of fatty acids including desaturation,
oxidation, uptake and incorporation into tissues and
conversion to eicosanoids are controlled by one or
more hormones. Conversely, studies in the last 4 – 5
decades have shown that the nature and level
of dietary fatty acids affect hormone secretion from
endocrine organs and, therefore, circulating
plasma levels. Major relationships between fatty
Fatty acids also alter hormone receptors by altering
lipid milieu, composition and fluidity of cell
membranes. In addition, many metabolic processes
altered by fatty acids or their metabolites, such as
platelet aggregation, activities of many enzymes and
metabolic disorders such as diabetes, atherosclerosis
and hypertension, have strong endocrine component.
Thus, significant interactions exist between fatty
acids and the endocrine system. This brief review will
attempt to elucidate: (1) the hormonal control of
fatty acid metabolism and (2) how fatty acids alter
hormone secretion from endocrine organs and their
biological actions on target tissues. In addition, a
special reference will be made to the interaction
between fatty acid and the endocrine system in
diabetes.

Correspondence: S. J. Bhathena, Phytonutrients Laboratory, BHNRC, ARS, USDA, Building 307-C, Room 225, Beltsville, MD 20705-
2350, USA. Tel: 1 301 504 8422. Fax: 1 301 504 9456. E-mail: bhathens@ba.ars.usda.gov

ISSN 1028-415X print/ISSN 1476-8305 online q 2006 Informa UK Ltd.

DOI: 10.1080/10284150600627128
2 S. J. Bhathena

Table I. Relationship between fatty acids and the endocrine
system.
Hormonal control of fatty acid metabolism
Synthesis and lipolysis
Desaturation and elongation
Oxidation and ketone formation
Eicosanoid production
Effects of fatty acids on hormones and neuropeptides
Plasma hormone levels
Neuropeptides in brain
Secretion
Receptors and membrane fluidity
Hormonal control of fatty acid metabolism
The hormonal control of FA metabolism is shown in
Figure 1 and has been reviewed in normal and diabetic
subjects (Liljenquist et al. 1974; Storlien et al. 1997;
Bhathena 1999; Saleh et al. 1999). The principal
hormones involved in lipogenesis and lipolysis which
control fatty acid concentration in plasma and tissues
are insulin, glucagon, catecholamines, cortisol and
growth hormone. Many other hormones also affect
fatty acid metabolism as shown in Figure 1. The levels
of these hormones are altered in diabetes, which
explains altered lipid metabolism in diabetes. Insulin
has multiple effects on lipid metabolism. Though
insulin stimulates lipogenesis (Beynen et al. 1982;
McTernan et al. 2002), its major effect is antilipolytic,
especially the inhibition of hormone-stimulated
lipolysis (Desai et al. 1973; McTernan et al. 2002).
Glucagon, catecholamines, cortisol and growth
hormone, which are counter regulatory hormones to
insulin, have predominantly lipolytic activity (Gerich
et al. 1976). However, glucagon, growth hormone and
catecholamines also have antilipolytic activity (David-
son 1987; Wu et al. 1988; Wahrenberg et al. 1989). In
humans, glucagon has only a marginal effect on
lipoprotein lipase (LPL), but it has a much stronger
effect in young animals. The lipolytic activity of
catecholamine is mediated via b-adrenoreceptors and
the antilipolytic effect is mediated through a-2-
adrenoreceptors (Leibel and Hirsch 1987; Pecquery
et al. 1988). The effects of these hormones on lipolysis
occur through hormone-sensitive lipase (HSL) that is
activated by cyclic adenosine monophosphate
(cAMP). Insulin stimulates phosphodiesterase,
which catabolizes cAMP and decreases cAMP level,
thereby inhibiting lipolysis.
Unlike HSL (TG lipase), insulin stimulates LPL.
Insulin also stimulates phospholipase C in adipose
tissue (Farese et al. 1986). In human adipocytes, LPL
is suppressed by tumor necrosis factor (TNF) in the
presence of insulin and dexamethasone (Fried and
Zechner 1989) but not in the absence of insulin (Kern
1988). Thus, TNF may be important in the
pathogenesis of hypertriglyceridemia. Insulin also

Figure 1. Hormonal control of fatty acid metabolism. Schematic diagram showing how different hormones control fatty acid metabolism in
intestine, adipose tissue, muscle and liver. “ þ ” indicates stimulatory (positive) effect and “ 2 ” indicates inhibitory (negative) effect on
different processes. Abbreviations: HSL, hormone sensitive lipase; LPL, lipoprotein lipase; Epi, epinephrine; NE, nor-epinephrine; GH,
growth hormone; Vaso, vasopressin; ACTH, adrenocorticotropic hormone; Cort, cortisol; TH, thyroid hormone; b-end, b -endorphin; Testo,
testosterone; TNF-a, tumor necrosis factor a; NO, nitric oxide; PG, prostaglandins; NPY, neuropeptide Y; Progest, progesterone; DHEA,
dehydroepiandrosterone; GLP-1, glucagon-like peptide 1; PP, pancreatic polypeptide; Aldo, aldosterone.
 Fatty acids and endocrine system 3

Table II. Insulin and fatty acid metabolism.

Adipose
# HSL ( # rate of lipolysis, # plasma FFA)
" FA and Triglyceride synthesis (re-esterification)
" Fatty acyl-CoA and fatty acyl transferase
" LP lipase ( " uptake of TG from plasma)
Liver
" FA and TG synthesis (de novo lipogenesis from glucose)
" VLDL formation ( " FAS and acyl-CoA carboxylase)
" Cholesterol synthesis Figure 2. Hormonal control of fatty acid synthesis in adipose
# Rate of FA oxidation and ketone formation ( # CAT-1) tissue. Note that insulin and counterregulatory hormones control
fatty acid synthesis via cAMP. “ þ ” indicates stimulatory effect and
Muscle
“ 2 ” indicates inhibitory effect. “?” the effect is not clearly
# Rate of FA oxidation ( # malonyl-CoA) established. Abbreviations: LP, lipoprotein lipase; TG, triglyceride
# Ketogenesis lipase.

hormones have significant effect on b or v oxidation of

fatty acids. However, increased v oxidation in diabetes
stimulates phospholipid synthesis in adipocytes indicates that the lack of insulin may be responsible
(Farese et al. 1982), hepatocytes (Cooper et al. (see below).
1990) and diaphragm and skeletal muscle (Ishizuka
et al. 1990). Various actions of insulin on fatty acid
metabolism in adipose, liver and muscle are summar-
Desaturation and elongation
ized in Table II. Figure 2 summarizes the hormonal
control of fatty acid synthesis in adipose tissue. Hormonal control of desaturases has been reviewed
Glucagon also has multiple effects on lipid metab- recently (Bezard et al. 1994; Dutta-Roy 1994; Ntambi
olism. It stimulates lipolysis by activating lipase (see 1995). There is indirect, as well as, direct evidence
above). It also stimulates LPL in muscle but not in that hormones control desaturation. Indirect evidence
adipose tissue (Geelan et al. 1980). In liver, glucagon comes from the alteration of fatty acid composition in
suppresses fatty acid synthesis and stimulates fatty diabetic, thyroidectomized, hypophysectomized and
acid oxidation (McGarry and Foster 1981). adrenalectomized animals where one or more hor-
A major consequence of increased FFA in diabetes mone is lacking. Figure 4 summarizes the stimulatory
in the face of decreased insulin is ketoacidosis. and inhibitory effects of various hormones on
Increased glucagon and decreased insulin will stimu- desaturation and elongation. Insulin plays an import-
late lipolysis in adipose tissue, producing FFA in ant role in desaturation. Insulin treatment in humans
plasma that is transported to liver. Decreased (Tilvis et al. 1986; el Boustani et al. 1989) as well as
availability of insulin reduces lipogenesis, and hence experimental diabetic animals (Gellhorn and Benja-
FFAs are converted to ketone bodies (acetoacetate min 1964; Eck et al. 1979; Prasad and Joshi 1979)
and b-hydroxybutyrate). Glucagon plays a critical role stimulates desaturases. Eck et al. (1979) reported that
in ketoacidosis. In normal subjects, infusion of
glucagon stimulates insulin secretion, and no rise in
ketones occurs. However, in diabetic subjects deficient
in insulin (IDDM), glucagon infusion produces a rise
in ketones (Liljenquist et al. 1974). Other hormones
counterregulatory to insulin, such as catecholamine,
also stimulate ketogenesis. However, an elevated ratio
of glucagon to insulin is the primary factor for
accelerated ketogenesis in diabetes (McGarry and
Foster 1977) as shown in Figure 3.
Recently leptin has been reported to increase fatty
acid oxidation and decrease fatty acid incorporation
into triglycerides in soleus muscle and thus oppose the
lipogenic effect of insulin (Muoio et al. 1997). Leptin
also increases fatty acid oxidation in cultured
pancreatic islets (Shimabukuro et al. 1997a,b).
Figure 3. Hormonal control of fatty acid metabolism in liver in
However, in obese, mildly diabetic Zucker rat, leptin diabetes. Increased glucagon/insulin ratio in diabetic state leads to
had no effect possibly due to mutation of the leptin stimulation of cAMP in liver leading to increased fatty acid
receptor. It is not established whether insulin or other oxidation and increase ketone production.
4 S. J. Bhathena
Figure 4. Hormonal control of fatty acid desaturation and elongation. The stimulatory and inhibitory effects of various hormones on
different desaturases and elongase are shown. Note that the hormonal control of D4 desaturase is not yet defined. Abbreviations: T3,
triiodothyronine; T4, thyroid hormone; Dex, dexamethasone; GH, growth hormone; ACTH, adrenocorticotropic hormone.
insulin increased D6 desaturase levels, yet arachidonic
acid (AA) decreased in the liver, which they suggested
could be due to increased utilization in excess of
increased synthesis by desaturase. Glucagon and
catecholamines, which antagonize the effect of insulin,
decrease desaturase activity (de Gomez Dumm et al.
1976, 1978; Brenner 1981). Desaturase activity is also
influenced by lipid lowering agents. Using a ratio of
20:4 –20:3 as an index of D5 desaturase activity,
Matsui et al. (1997) showed that bezafibrate increases
D5 desaturase activity and thereby improving insulin
sensitivity.
Insulin has been shown to stimulate as well as
inhibit D9 desaturase. Estrogens, triiodothyronine and
synthetic glucocorticoid, dexamethasone, stimulate
D9 desaturase (Marra and de Alaniz 1995; Stanton
et al. 2001) while thyroid hormone and growth
hormone inhibit it (Gueraud and Paris 1997). In
obese women insulin stimulates D5 desaturase (41A).
Insulin and thyroxine also stimulate D5 and D6
desaturases while catecholamines, glucagon, aldoster-
one, adrenocorticotropic hormone (ACTH) and
dexamethasone inhibit both desaturases. Thus,
decreased insulin and increased glucagon in diabetic
subjects would account for decreased desaturase
activity in diabetes. However, Lui et al. (41B) reported
increased D6 desaturase activity in diabetes. Testos-
terone, aldosterone and corticosterone inhibit D5
desaturase in HTC cells (Marra et al. 1988). The
hormonal control of D4 desaturase is not well defined.
D4 desaturase is also involved in the conversion of EPA
to DHA in brain (Anderson et al. 1990). However, it is
not clear whether any hormone or neuropeptide play a
role in its modulation in brain. The TFAs of the v9
family (18:1v9) inhibit D6 desaturase involved in the
conversion of linoleic acid to gamma linolenic acid
(GLA) in the liver and heart but have no effect on D5
desaturase in the v6 family. Others have reported that
TFAs also inhibit A5 desaturase and can also inhibit
cyclooxygenase and lipooxygenase and thereby
decrease eicosanoid production. They also decrease
D9 desaturase (Hill et al. 1982). Thyroxine has been
shown to stimulate elongase in liver microsomes but
not in mitochondria. The effects of other hormones on
elongases have not been reported.
Oxidation
In human muscle, oxidation of long chain fatty acids is
controlled by glucose plus insulin via regulation of
entry into mitochondria. However, mitochondrial
uptake and oxidation of medium chain fatty acids is
not dependent on glucose and/or insulin (Sidossis et al.
1996). In diabetes, owing to the lack of insulin,
oxidation of glucose is reduced and is compensated by
increased oxidation of fatty acids. The ratio of fatty
acid oxidation to esterification is higher in streptozo-
tocin diabetic rats than in control animals and is not
significantly affected by insulin treatment (Moir and
Zammit 1994).
It is not clear whether insulin or other hormones
have significant effects on b or v oxidation of fatty
acids. However, increased v oxidation in diabetes
indicates that the lack of insulin may be responsible.
By reducing lipolysis and glycogenolysis, insulin
enhances the relative contribution of carbohydrate
oxidation and reduces fat oxidation in resting state as
well during exercise in diabetic rats (Houwing et al.
1995). The hormonal control of fatty acid oxidation in
diabetes, therefore, needs to be addressed. Shimabu-
kuro et al. (1997a,b) reported increased FFA
oxidation in cultured islets by leptin. However, in

Figure 5. Role of hormones in eicosanoid formation. Most
hormones affect eicosanoid formation by controlling lipolysis of
phospholipids. Insulin and nor epinephrine act on the
cyclooxygenase and lipooxygenase. The different PLA2s involved
are cPLA2, cytosolic PLA2 which is Caþ þ dependent; IPLA2,
cardiac PLA 2 which is Caþ þ independent; and spPLA2,
sarcoplasmic PLA2. Abbreviations: PLA2, phospholipase A2; PLC,
phospholipase C; Dex, dexamethasone; LCFA, long chain fatty
acids; cyt p450, cytochrome p450; CO, cyclooxygenase; LO,
lipooxygenase; PGG2, prostaglandin G2; HETE, hydro-
xyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic
acid.
islets of obese, mildly diabetic Zucker rat leptin had no
effect possibly due to mutation of leptin receptor.
Eicosanoid synthesis
Eicosanoids are formed from long chain PUFA. The
hormonal control of eicosanoid occurs during the
conversion of phospholipids to long chain PUFA by
phosholipases (Figure 4). Insulin acts directly on
cyclooxygenase and stimulates the conversion of AA
to prostaglandin G2 (PGG2) which is then converted
to various prostanoids. Epinephrine, bradikinin and
angiotensin-II (A-II) stimulate phospholipase A2 and
phospholipase C (Vane 1976; Van Den Bosch 1980;
Shukla 1982) while cortisol and synthetic glucocorti-
coids, dexamethasone and prednisone, inhibit the
lipases (Blackwell et al. 1980). They appear to act via
lipocortin. Histamine and thrombin also stimulate
these lipases. TNF has been shown to stimulate
prostaglandin synthesis (Burch and Tiffany 1989).
The interactions between hormones and prostanoids
have been reviewed by Myers et al. (1989).
Role of neuropeptides in fatty acid release
Widmaier (1997) and Yehuda et al. (1998) have
reviewed the role played by neuropeptides in the
release of fatty acids, especially in brain. Thyrotropin
releasing hormone (TRH), vasoactive intestinal pep-
tide (VIP), growth hormone releasing factor (GRF)
and angiotensin-II (A-II) stimulate the release of AA
from pituitary cells in culture either by increasing
intracellular Caþ þ or by stimulating phospholipases.
Fatty acids and endocrine system 5
Dopamine (DA) inhibits the A-II and TRH stimu-
lated release of AA (Canonico 1989). Somatostatin
has been reported to block the fatty acid turnover in
brain by decreasing triglyceride lipase (Catalan et al.
1986). It also decreases fatty acid incorporation into
phospholipid. Gonadotropin releasing hormone
(GnRH) also increases release of AA and stimulates
lipooxygenase and epoxygenase pathways. In man, AA
metabolism is modulated by catecholamines (Kertula
et al. 1995). Thus, norepinephrine (NE) inhibits
thromboxane production (cyclooxygenase pathway)
and stimulates leukotriene production (lipooxygenase
pathway) while DA tends to increase the production of
prostacyclin, leukotriene and PGE2 (Figure 5).
Effects of fatty acids on hormones
The effect of type of dietary fatty acids on insulin
action is reviewed by Storlien et al. (1997). High
intake of saturated fat appears to produce hyperinsu-
linemia and increases risk of diabetes (Bhathena
1999). PUFA appear to have the opposite effect. In
monkeys, Barnard et al. (1990) reported that, unlike
cis isomers, TFA had no effect on erythrocyte
membrane fluidity but affected insulin receptors by
decreasing the number and increasing the affinity, an
effect similar to that observed with saturated fatty
acids in rabbits (Ginsberg et al. 1979; Gould et al.
1982; Berlin et al. 1989). In brain TFA are less potent
in inhibiting binding of opiates to their receptors and
in decreasing membrane viscosity compared to
corresponding cis fatty acids. Studies of the effects of
TFA on lipid profile and insulin and other hormones
in diabetic subjects are lacking. Elevated FFA in
plasma in diabetes and other disorders results in
hypercorticoidism and initiates a positive feedback
loop between adipocytes and hypothalamic – pitu-
itary – adrenal axis (Widmaier et al. 1995).
Several studies have shown that saturated fatty acids
increase plasma insulin level and insulin response
(Folsom et al. 1996; Rasmussen et al. 1996).
Saturated fatty acid (palmitate) also increases glucose
induced insulin release but not basal release which is
reversed by epinephrine. Palmitate appears to act via
increasing calcium flux and the mobilization of
intracellular calcium (Warnotte et al. 1994). Though
saturated fatty acids stimulate glucose transport in
isolated rat adipocytes acutely, prolonged treatment
induces insulin resistance via post receptor defect
(Hunnicutt et al. 1994). The stimulation of glucose
transport by saturated fatty acids in adipocytes is via
stimulation of insulin receptor autophosphorylation
(Hardy et al. 1991). Free fatty acids appear to
stimulate insulin release (Crespin et al. 1973) and
inhibit glucagon release (Madison et al. 1968) from
pancreatic islets. However, long term exposure of
islets to high levels of FFA results in beta cell
dysfunction and diminishes glucose induced insulin
6 S. J. Bhathena
secretion (Zhou and Grill 1994; Girard 1995; New-
gard and McGarry 1995; Hirose et al. 1996). In
pubertal IDDM subjects insulin has no significant
effect on plasma FFA (Caprio et al. 1994).
Nitric oxide (NO) has been suggested to play a role
in FFA induced insulin secretion since in cultured
islets from prediabetic Zucker fatty diabetic rats, FFA
induced significant rise in NO and reduced insulin
secretion (Shimabukuro et al. 1997a,b). Elevated FFA
in plasma in diabetes and other disorders results in
hypercorticoidism and initiates a positive feedback
loop between adipocytes and hypothalamic – pitu-
itary – adrenal axis (Widmaier et al. 1995). An
abnormality in thyroid function and altered thyroid
hormone levels have been reported in diabetic subjects
and that dysfunction of the hypothalamic – pituitary –
thyroid axis may be involved (Suzuki et al. 1994).
Fatty acid binding proteins
A relationship exists between fatty acid binding
proteins (FABP) and the endocrine system. FABP
decreases in the aorta of streptozotocin diabetic rats
and is reversed by insulin treatment (Sakai et al.
1995). It has been suggested that FABP2 or a tightly
linked gene may be associated with insulin resistance
(Mitchell et al. 1995).
Effects of fatty acids on neuropeptides
Saturated as well as unsaturated fatty acids have been
shown to play a role in neuropeptide synthesis, release
and function. A unique characteristic of fatty acids is
that they can cross the blood brain barrier. However,
saturated and unsaturated fatty acids are transported
into the brain by two different transport systems. Fatty
acids of v6 and v3 series are more active than
saturated fatty acids or those of v9 series in
modulating neuropeptides. Fatty acids may act either
directly or through their metabolites; e.g. many
actions of AA on neuropeptides are through eicosa-
noids. The effect on hormone action in many cases is
by controlling fluidity of neuronal membranes which
then impact on neuropeptide function by altering the
binding to their receptors and by altering ionic
channels. The effects of fatty acids on neuropeptides
have been reviewed by Widmaier (1997) and Yehuda
et al. (1998).
Both linoleic and oleic acids increase basal release of
luteinizing hormone (LH) from pituitary cells (Barb
et al. 1995). However, oleic acid suppresses LH
release stimulated by GnRH (Barb et al. 1995). Oleic
acid also inhibits basal growth hormone secretion
from anterior pituitary cells (Kennedy et al. 1994) and
somatostatin mRNA level and secretion from hypo-
thalamic and cortical cells (Senaris et al. 1993).
Saturated fatty acids, present in beef tallow reduces
noradrenergic function in brain compared to unsatu-
rated fatty acids of safflower oil (Matsuo et al. 1995).
Long-chain unsaturated fatty acids, but not
saturated fatty acids, stimulates neurotensin release
from enteric cells (Barber et al. 1991) and prolactin
release in cultured pituitary cells and pituitary gland
incubated in vitro (Canonico et al. 1985). The
increased prolactin release appears to be due to
calcium influx (Roudbaraki et al. 1995). In rat striated
synaptosomes, AA stimulates the release and inhibits
the uptake of DA (L’hirondel et al. 1995). AA is also
involved in basal and DA and GnRH stimulated
growth hormone release from pituitary cells (Chang
et al. 1996). Though AA has no effect on thyrotropin
(TSH) secretion from pituitary, its metabolites
derived via lipooxygenase pathway stimulate TSH
release from anterior pituitary cells (Canonico et al.
1984). Similarly 12-hydroperoxy arachidonate stimu-
lates the release of LH and follicular stimulating
hormone (FSH) (Ikawa et al. 1996) and prolactin
(Judd et al. 1988) from anterior pituitary cells. AA as
well as its metabolite PGE2, derived via cyclooxygen-
ase pathway increase b-endorphin level in pituitary
(Paneti et al. 1989). Prostaglandins derived from AA
are also involved in the metabolism and function of
neurotransmitters and steroids. EPA and DHA reduce
progesterone production from luteal cells (Hinckley
et al. 1996). PUFA also affects binding of opiod
peptides, enkephalin and B-endorphin, to their
receptors (Myers and Freire 1985; Schwyzer 1988;
Hargreaves and Clandinin 1990).
v3 Fatty acids also modulate neurotransmission in
brain. Thus, a-linolenic acid deficiency decreases DA
and dopaminergic receptors and serotonin receptors
but not the serotonin level in frontal cortex (Delion
et al. 1996). DHA also increases DA uptake by the
brain (Shashoua and Hesse 1996). Similarly a role in
synaptogenesis in the brain has been postulated for
DHA (Vidyanathan et al. 1994). Alpha linolenic acid
and EPA have been shown to reduce TNF-a and
interleukin-1b (IL-1b) production in humans
(Caughey et al. 1996). Importantly, several studies
have reported that the ratio of v6/v3 fatty acids is
more important in the modulation of endocrine and
neuroendocrine systems than the concentration of
individual PUFA (Yehuda et al. 1998).
Eicosanoids as endocrine system
Though eicosanoids are not hormones in the classical
sense, they have hormone-like effects. Hormones act
locally in the gland where they are produced as well as
transported to target organs where they produce their
metabolic effects. Unlike hormones, eicosanoids are
not transported from the tissues where they are
produced to the target site. Instead, they act locally to
produce biological effects, i.e. at the level of platelets,
endothelial cells and leukocytes and are involved in

Figure 6. Role of insulin and prostanoids in platelet aggregation in
normal state. Under physiologic (normal) condition, insulin
stimulates prostacyclin in endotheliam and in platelets which in
turn inhibit platelet aggregation. Abbreviations: PGI2, prostacyclin;
IR, insulin receptor; A2-adreno R, A2 adrenergic receptor; NO,
nitric oxide; EDRF, endothelium-derived relaxing factor.
controlling blood pressure, inflammatory processes,
immune function and regulation of hormones. Thus,
they are considered localized hormones. Several
studies indicate that eicosanoids are also produced in
the brain and act locally to modulate central nervous
system function.
Prostaglandins also play a role in insulin secretion.
Sodium salicylate, which inhibits cyclooxygenase and
thereby decreases PG synthesis, increases basal as well
as glucose-stimulated insulin secretion in diabetic
subjects, indicating involvement of PG. Robertson
and Chen (1997) infused PGE2 in normal humans
and inhibited acute insulin response to glucose. In
addition, PGs are also involved in abnormal collagen
metabolism in diabetes (Yue et al. 1985). Recently,
bradykinin has been shown to stimulate phospholipids
to release AA which is then metabolized via
cyclooxygenase, lipooxygenase and cytochrome P450
to yield vasoactive products (Quilley et al. 1994).
In diabetic subjects who consume large quantities of
fish oil, the situation is different. There is an increase
in thromboxane A3 (TXA3) and Prostacyclin (PGI3)
synthesis and decreased TXA2 and prostaglandin
(PGI2) owing to the decreased availability of AA and
the competition of the v3 fatty acids from fish oil.
Thus, because of the decreased TXA2 and PGI2 and
the increased PGI3 and inactive TXA3, there is less
platelet aggregation, which is beneficial for diabetic
subjects with coronary artery disease and hyperten-
sion (Beitz et al. 1986; Tilvis et al. 1987; Leaf and
Weber 1988; Knapp and FitzGerald 1989; Nishikawa
et al. 1997). Figures 6 and 7 summarize the role of
hormones, hormone receptors and prostanoids in
platelet aggregation in normal and diabetic states.
Leukotrienes formed by lipooxygenase are also
biologically active. LT5 formed from v3 fatty acids is
more active in immune functions in humans (Kelley
et al. 1991). Neutrophils and monocytes increase LT
formation from EPA more than from AA (Lee et al.
1985). This explains the beneficial effects of fish oil on
Fatty acids and endocrine system 7
Figure 7. Role of insulin and prostanoids in platelet aggregation in
diabetes. In diabetic state, decreased availability of insulin leads to
decreased prostacyclin in endothelium and platelets which results in
increase platelet aggregation. Abbreviations: PGI2, prostacyclin; IR,
insulin receptor; A2-adreno R, A2 adrenergic receptor; NO, nitric
oxide; TXA2, thromboxane A2; ADP, adenosine diphosphate.
immune function in low-dose streptozotocin diabetic
mice in which fish oil decreased the number of class II
antigen-expressing cells in pancreatic islets (Linn et al.
1989).
In summary, there is a close relationship between
fatty acids and the endocrine and neuroendocrine
system. Altered lipid metabolism in diabetes is
dependent, in large part, on altered endocrine system.
The interactions between fatty acids and endocrine
system occur in many tissues, liver, adipose, muscle
and also in brain. Since fatty acid metabolism is
altered in diabetes, several processes in which fatty
acids and hormones are involved are also altered in
diabetes, such as platelet aggregation, immune
function and neuronal development in the brain.
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