Exposure to lipid-rich follicular ﬂuid
is associated with endoplasmic
reticulum stress and impaired oocyte
maturation in cumulus-oocyte
Xing Yang, M.D., Ph.D.,
Linda L. Wu, Ph.D.,
Lindsay R. Chura,
Xiaoyan Liang, M.D.,
Michelle Lane, Ph.D.,
Robert J. Norman, M.D.,
and Rebecca L. Robker, Ph.D.
Reproductive Medical Center, Sixth Afﬁliated Hospital of Sun Yan-sen University, Guangzhou, People's Republic of China; and
Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia
Objective: To determine whether the high lipid content of human follicular ﬂuid inﬂuences oocyte maturation.
Design: Mouse oocytes as substitutes for human oocytes were exposed to follicular ﬂuids of differing lipid content with outcome monitoring.
Setting: Private infertility clinic and university laboratory.
Patient(s): Seventy-four women seeking assisted reproduction, and gonadotropin-stimulated mice.
Intervention(s): Assay of follicular ﬂuids for triglyceride and free fatty acids, and stimulation of mouse cumulus-oocyte complexes (COCs) to maturity
in vitro in the presence of lipid-rich or lipid-poor follicular ﬂuid.
Main Outcome Measure(s): Oocyte lipid content, expression of endoplasmic reticulum stress marker genes, and oocyte maturation assessed in mouse
COCs exposed to lipid-rich follicular ﬂuid were compared with complexes exposed to lipid-poor follicular ﬂuid and complexes matured in vivo.
Result(s): Follicular ﬂuids were obtained from women of known body mass index undergoing oocyte aspiration at a private infertility clinic, and the
follicular ﬂuids were assayed for triglyceride and free fatty acids; those with the highest and lowest levels of these lipids were selected. The mouse COCs
exposed to lipid-rich follicular ﬂuid during their maturation had increased oocyte lipid content, induction of endoplasmic reticulum stress markers, and
impaired oocyte nuclear maturation.
Conclusion(s): Increased body mass index is associated with elevated triglycerides and free fatty acids in ovarian follicular ﬂuid. Maturation within this
lipid-rich environment is detrimental to oocytes. (Fertil Steril
2012;97:1438–43. Ó2012 by American Society for Reproductive Medicine.)
Key Words: ATF4, ATF6, endoplasmic reticulum stress, free fatty acids, GRP78, lipotoxicity, obesity, triglyceride
besity in women is associated
with reduced conception rates
(1–3), even when oocytes are
fertilized in vitro (4–8). Studies in
female mice more clearly demonstrate
that obesity induced by a high-fat diet
affects oocyte quality, resulting in oo-
cytes that when fertilized in vivo are
slower to develop to blastocysts and
exhibit a skewed trophectoderm and
inner cell mass ratio (9). Oocytes from
obese mice also have increased lipid
content (10), alterations in mitochon-
drial activity (10, 11), and evidence of
endoplasmic reticulum stress (10);these
cellular responses likely contribute to
the increased granulosa cell apoptosis
(10, 12) and decreased rates of oocyte
nuclear maturation (12) and fertilization
(10). This accumulating evidence of
associations between diet-induced obe-
sity and altered oocyte quality in mice
does not, however, demonstrate whether
similar cellular changes occur in the
oocytes of obese women. Further, it is
currently unclear whether the effect of
obesity on oocytes is instigated during
their growth and folliculogenesis or is
a result of acute events immediately
Periconception oocyte maturation
is initiated when a large antral follicle
receives the luteinizing hormone (LH)
surge. While the cumulus cells sur-
rounding the oocyte rapidly produce
the viscous extracellular matrix nec-
essary for ovulation and fertilization,
the oocyte resumes meiosis and ex-
trudes its ﬁrst polar body. Physiolog-
ically this process occurs within the
conﬁnes of the ovarian follicular
Received September 30, 2011; revised and accepted February 23, 2012; published online March 20,
X.Y. has nothing to disclose. L.L.W. has nothing to disclose. L.R.C. has nothing to disclose. X.L. has
nothing to disclose. M.L. has nothing to disclose. R.J.N. has nothing to disclose. R.L.R. has nothing
Supported by grants from the National Health and Medical Research Council of Australia (to R.J.N.
and R.L.R.) and the National Natural Science Foundation of China (grant no. 30973202 to X.Y.).
Reprint requests: Rebecca L. Robker, Ph.D., School of Paediatrics and Reproductive Health, University
of Adelaide, Medical School North, Level 2, Adelaide, South Australia, 5005, Australia (E-mail:
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