Sex differences in the physiology of eating

Abstract

Hypothalamic-pituitary-gonadal (HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-α (ERα) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating.

Keywords: eating disorders; estrogens; neuroendocrinology; obesity; testosterone.

Figures

Fig. 1.

The principal pathways of human gonadal steroid hormone synthesis. Molecules are shown in standard line-angle diagrams, and enzymes are represented as numbered arrows, with the major pathway in adult gonads circled. Steroidogenesis begins with the cleavage of the 6 C side chain from cholesterol (C27H46O) by the mitochondrial cholesterol side-chain cleavage enzyme, otherwise known as P-450scc or CYP11A1 (arrow 1) to yield pregnenolone (C21H32O2). Note that it and other progestins (or progestagens; labeled in blue, with the structure of progesterone, the principal progestin, also in blue) are 21 C molecules. Subsequent steps occur on the smooth endoplasmic reticulum. Progestins are metabolized to androgens (labeled in red, with the principal androgen, testosterone, diagrammed in red), which are 19 C, and to mineralocorticoids and glucocorticoids (not shown), which are 21 C. Androgens are metabolized to estrogens (labeled in green, with the principal estrogen, estradiol, diagrammed in green), which are 18 C. Note that all of these steroids retain the basic 17 C “gonane” structure, consisting of three cyclohexane rings and one cyclopentane ring, but differ in the attached side groups and oxidation states of the rings. An additional estrogen, estriol (not shown), is synthesized in significant amounts only by the placenta and fetal liver. Other labeled enzymes: 2, 17α-hydroxylase; 3, 17, 20-lyase; 4, 17β-hydroxysteroid dehydrogenase;5, 3β-hydroxysteroid dehydrogenase; 6, 5α-reductase; 7, aromatase; 8, 21-hydroxylase.

Fig. 2.

Plasma levels of LH, FSH, estradiol, and progesterone during the 4-day ovarian cycle of rats maintained under 12:12-h light-dark cycle. Ovarian cycle days, labeled on the basis of vaginal cytology and beginning at dark onset, are diestrus 1 (D1), diestrus 2 (D2), proestrus (P), and estrus (E). Values are smoothed averages based on several sources (101, 114, 444, 511, 684). Solid bars along x-axis indicate nocturnal periods. LH levels are presented as fold increases over basal (= 1) because published proestrous peak concentrations vary >20-fold. Estradiol's molecular weight is 272 and progesterone's is 314. Hormone concentrations during the additional day in 5 day-cycling rats are similar to those in diestrus 1 (282). The pattern may vary slightly in rats maintained under 14:10-h light-dark cycle (90). The hatched rectangle at the bottom right of the figure indicates the period during which estrous vaginal smears occur most regularly.

Fig. 3.

Plasma levels of LH, FSH, estradiol, and progesterone during the human ovarian cycle. Cycle phases, labeled with respect to the LH peak, are follicular (F), periovulatory (PO), and luteal (L). The follicular phase begins with menses, and the LH peak and ovulation occur ∼14 d later. Longer menstrual cycles are usually caused by prolonged follicular phases. Values are smoothed averages based on several sources (97, 617, 638, 735).

Fig. 4.

Plasma estradiol concentration during chronic, cyclic estradiol treatment. Plasma samples were taken in the 9th cycle of subcutaneous injection of 2 μg estradiol benzoate (EB) once each 4th day, at the middle of the light phase of day 2 (D2, arrow), which models diestrus 2 in intact rats. D4 of the treatment regimen modeled estrus based on maximally decreased eating behavior and increased sexual receptivity in progesterone-primed rats. Values below the detection threshold of our radioimmunoassay (30 pmol/l) are shown as 30 pmol/l. Reprinted from Hormones and Behavior, Cyclic estradiol treatment normalizes body weight and restores physiological patterns of spontaneous feeding and sexual receptivity in ovariectomized rats, 42: 461–471, 2002; republished with permission from Elsevier; from Asarian and Geary (15).

Fig. 5.

Developmental effects of both gonadal sex (testes or ovaries) and chromosomal sex (XX or XY) affect food intake. Mice were gonadectomized 4 wk before testing to eliminate the activational effects of sex hormones. Note that 1) during the dark phase (left), gonadal females ate more than gonadal males, regardless of their chromosomal sex, and 2) during the light phase (right; note altered scale), gonadal and chromosomal females (XX) ate more than all other groups; these mice also had an approximately twofold more fat mass (not shown). Tests (not shown) of mice with XO and XXY chromosomes indicated that these effects were due to X-gene dosage, not the presence of the Y chromosome. *P < 0.05; **P < 0.01. Republished with permission from Chen et al. (122).

Fig. 6.

Cyclic estradiol benzoate (EB) treatment models the endogenous cycle and maintains normal patterns of body weight gain, daily food intake, and spontaneous meal size in ovariectomized (OVX) rats. A: OVX increased and cyclic estradiol treatment normalized body weight. Data to left of the solid vertical lines are from the last ovarian cycle before OVX (x-axis labels appear in panel B: Preovx; D1, diestrus 1, D2 diestrus 2; P, proestrus; E, estrus), and data to the right of the solid vertical lines are sham-operated intact rats (solid circles), OVX rats treated with EB (triangles), and OVX rats treated with the oil vehicle (open circles); dashed vertical lines divide the numbered 4-day treatment cycles (days 1–4), which are aligned so that the last day of each cycle is the second day after EB injection, the day that models estrus. B: OVX increased and cyclic estradiol treatment normalized daily food intake (x-axis labels explained above). Note 1) that OVX elevated, and EB normalized, the basal level of daily food intake (tonic estrogenic inhibition of eating; tested on day 2) and 2) that OVX eliminated, and EB reinstated, the drop in food intake during estrus in intact rats and on cycle day 4 in OVX rats (phasic or cyclic estrogenic inhibition of eating). C: OVX increased and cyclic estradiol treatment normalized nocturnal spontaneous meal size. Triangles indicate mean meal sizes during the last cycle Preovx (abbreviations as above); solid circles indicate mean Postovx meal sizes during cycles 2–7 of cyclic EB treatment (injection time indicated by arrow); and open circles indicate mean Postovx meal sizes in control rats treated with the oil vehicle. +Significantly different from intact rats and EB-treated rats on day 2; *Significantly different from diestrus 2 (intact group) or day 2 (OVX group). Meal frequency was not increased by OVX or decreased by EB (data not shown). Reprinted from Hormones and Behavior, Cyclic estradiol treatment normalizes body weight and restores physiological patterns of spontaneous feeding and sexual receptivity in ovariectomized rats, 42: 461–471, 2002; republished with permission from Elsevier; from Asarian and Geary (15).

Fig. 7.

Daily food intake during the ovarian cycle in women (A) and rhesus macaques (B). Note the progressive decreases in food intake during the follicular phase in both women and monkeys and the high, constant levels of food intake during most of the luteal phase in monkeys (women's data were averaged across the entire luteal phase). Women's data (kilocalories eaten per day; values are expressed as means ± SE) are calculated from three studies in which food intake was measured by weighing, and the cycle phase was monitored with urinary LH and reports of menses in a total of 34 women. In each study, data were averaged across the early-follicular (eF; 4 day), midfollicular (mF; ∼9 day), periovulatory (PO; 4 day), and luteal (L; ∼11 day) phases. *Significantly different from luteal phase. Adapted from Am. J. Clin. Nutr. (1993; 57: 43–46), American Society for Nutrition (229); Am. J. Clin. Nutr. (1989; 49: 252–258), American Society for Nutrition (278); and Am. J. Clin. Nutr. (1989; 49: 1164–1168), American Society for Nutrition (450). Monkey data are plasma LH concentrations (open circles, means ± SE) and daily food intakes (solid bars, means ± SE) averaged across consecutive 3-day intervals relative to the LH peak (day 0) in 7 monkeys. *Significantly different from day −2/0. Reprinted with permission from Human Reproduction Update, Brain imaging studies of appetite in the context of obesity and the menstrual cycle, Dean A. Van Vugt, 16: 276–292, 2010 (756).

Fig. 8.

Estradiol treatment reduced daily food intake (A) and body weight gain (B) in ovariectomized wild-type (WT) mice, but not in Erα−/− mice. Constant-release estradiol pellets that produced plasma estradiol levels near the proestrous maximum or control vehicle pellets were subcutaneously implanted during ovariectomy. Data are from days 8–25 postoperatively because mice regained their presurgical weights by day 8. *Significantly less than control WT mice. Republished with permission from Geary at al. (257).

Fig. 9.

Estradiol treatment reduced nocturnal spontaneous meal size (A) and body weight gain (B) in ovariectomized control rats, but not in ovariectomized rats that received bilateral injections of adenovirus-vectored anti-ERα siRNA in the caudal medial nucleus of the solitary tract (cmNTS) (ERαKD; control rats received cmNTS injections of antiluciferase siRNA). Rats received subcutaneous injections of 2 μg estradiol benzoate (EB) or the oil vehicle (Oil) each 4th day. Meal sizes are averages of data from the cycle day of the estradiol treatment regimen that modeled estrus, from cycles 5–9; this day should reflect both the cyclic and the tonic effects of estradiol. Body weight gains are from surgery through cycle 9. *Significantly less than oil-treated rats that received the control siRNA (19, 20).

Fig. 10.

Frequency histograms of the density of fungiform papillae on the anterior tongue in 23 men and 25 women. A 2 × 2 χ2-test indicated that the sex difference in distributions was significant; note that ∼40% of the women sampled had more than 100 FP/cm2 vs. only ∼5% of men. Reprinted from Physiology and Behavior, PTC/PROP tasting: anatomy, psychophysics, and sex effects, Linda M. Bartoshuk, Valerie B. Duffy, Inglis J. Miller, 56: 1165–1171, 2002; republished with permission from Elsevier; from Bartoshuk et al. (46).

Fig. 11.

Cyclic changes in the eating-stimulatory effect of ghrelin in rats. The estrous cycle was monitored in intact rats (D1, diestrus 1; D2, diestrus 2; P, proestrus; E, estrus), and third cerebroventricular injections of 0.1 nmol of ghrelin or saline were tested on each cycle day. Ghrelin stimulated eating only on D1 and D2. *Significantly different from saline, same cycle day. Reprinted with permission from the American Diabetes Association from Diabetes, Deborah J. Clegg, Lynda M. Brown, Jeffrey M. Zigman, Christopher J. Kemp, April D. Strader, Stephen C. Benoit, Stephen C. Woods, Michela Mangiaracina, and Nori Geary, 56: April 2007; from Clegg et al. (130).

Fig. 12.

Sex differences in the satiating effect of endogenous CCK in rats, assessed with the CCK-1 receptor antagonist devazepide. A and B: intact female rats were maintained in cages permitting recording of spontaneous meal patterns and were undisturbed except for daily injections of vehicle (Veh) or 1 mg/kg devazepide (Dev) 1 h before dark onset on the day of diestrus 2 or estrus. Note that devazepide significantly increased meal size during estrus (*P < 0.05), but not during diestrus, and that devazepide did not alter nocturnal meal frequency. Further tests indicated that the effect of devazepide did not depend on the smaller control meal sizes during estrus than diestrus 2 (data not shown). Reprinted from Peptides, Endogenous cholecystokinin's satiating action increases during estrus in female rats, Lisa A. Eckel and Nori Geary, 20: 451–456, 1999; republished with permission from Elsevier; from Eckel and Geary (204). C: intakes of 0.8 M sucrose during minute 5–45 in chronically estradiol-treated and control, oil-treated ovariectomized rats that sham fed with open gastric cannulas, were acutely pretreated with devazepide (Dev) or saline and received intraduodenal infusions of 10% Intralipid (0.44 ml/min) or saline (SAL) from minute 5 to 15. Note that estradiol increased the eating-inhibitory effect of Intralipid (*P < 0.05) and that this was completely reversed by Dev (+P < 0.05). From Asarian and Geary (17). D: devazepide-induced increases in nocturnal food intake (means ± SE) in female rats that were injected with 1 mg/kg devazepide every second day, according to a random schedule, and were tested for vaginal opening (puberty) daily, starting at 22 days of age. Puberty occurred at 30 ± 1 day of age, and rats cycled regularly thereafter, as indicated by observation of vaginal estrus every 4th or 5th day. Data are shown as mean intakes prior to puberty and on days of estrus in each week after puberty (devazepide had no effects on other days; data not shown). Note that devazepide increased food intake only after puberty. (*Significantly different from saline on matched test days, P < 0.05; **P < 0.01) (455).

Fig. 13.

Male-female sex differences in the effects of transgenic deletion of the melanocortin 4 receptor gene (Mc4r−/−) on eating and weight gain in mice. Male and female Mc4r−/− and wild-type (WT) mice were fed a low-fat diet (LFD) from weaning to age 12 wk and then a high-fat diet (HFD) until week 22. Data are means of food intakes (kJ/day) ± SE and were measured for low-fat diet (LFD) from age 7 to 12 wk (top) and a high-fat diet (HFD) from age 12 to 22 wk (middle). Bottom: body weight gains (g, means ± SE) between week 7, when all mice had similar weights, to week 22. Note that female Mc4r−/− apparently increased food intake relative to female WT mice more than male Mc4r−/− mice on both diets and gained more weight than males (although the authors reported significant main effects of sex in their ANOVA, they did not test these relative differences for significance). Republished with permission of the Endocrine Society, from Endocrinology, Gregory M. Sutton, James L. Trevaskis, Matthew W. Hulver, Ryan P. McMillan, Nathan J. Markward, M. Josphine Babin, Emily A. Meyer, and Andrew A. Butler, 147: 2186–2006, 2006; permission conveyed through Copyright Clearance Center, Inc.; from Sutton et al. (712).

Fig. 14.

Agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons are necessary for the periovulatory decrease in eating in mice. Mice in which AgRP and NPY neurons were transgenically deleted (solid squares) did not show an estrous decrease in daily food intake under conditions in which wild-type control mice did (open symbols). M, diestrus 1; D, diestrus 2; P, proestrus; E estrus. From Olofsson et al. (527).

Fig. 15.

Male-female and estrogen-controlled sex differences in hedonics in rats. A: intact male rats licked more 0.025 and 0.05 M sucrose than intact females, and estradiol-treated ovariectomized females licked more than control, oil-treated females in 10-s palatability tests; neither sex difference was detected in tests of higher sucrose concentrations. Solid squares denote intact male rats, while open circles denote oil-treated ovariectomized females (OVX-OIL), and gray circles denote estradiol-treated ovariectomized females (OVX-EB). aSignificantly different from OVX-OIL. bSignificantly different from OVX-EB. B: overnight intake of 0.025 M sucrose in the same rats, expressed as ml/100 g body wt; abbreviations are the same as above. That males drank more independent of their greater size suggests that the hedonic difference shown in A controlled intake. In contrast, the effect of estradiol on palatability did not influence overnight intake. *Significantly different from both groups of ovariectomized females. A and B: Reprinted from Physiology and Behavior, Sex differences in behavioral taste responses to and ingestion of sucrose and NaCl solutions by rats, Kathleen S. Curtis, Linda M. Davis, Amy L. Johnson, Kelly L. Therrien, Robert J. Contreras, 80: 657–664, 2004; republished with permission from Elsevier; from Curtis et al. (152). C: intact rats tested during estrus (E/SAL, triangles) licked less 0.025 M sucrose solutions in 10-s palatability tests than rats tested during diestrus 2 (D2/SAL, circles). Intakes of 0.05–0.4 M sucrose solutions did not differ, suggesting that they were similarly palatable, and the effect obtained during the brief-access testing did not translate into an overnight effect (data not shown). aSignificantly different from diestrus, same sucrose concentration. Reprinted from Physiology and Behavior, vol. 86, Deann P. D. Atchley, Karen L. Weaver, and Lisa A. Eckel, Taste responses to dilute sucrose solutions are modulated by stage of the estrous cycle and fenfluramine treatment in female rats, 265–271, 2005, with permission from Elsevier; from Atchley et al. (23). D: estradiol failed to decrease 45-min sham intake of a 6.25% corn oil emulsion in ovariectomized rats, although estradiol significantly decreased real intake of the same solution; abbreviations are the same as in A. Rats received 2 μg estradiol benzoate or control injections once each 4th day and were tested on the day modeling estrus. *Significantly different from real intake in control rats. (Asarian L, Mangiaracina M, and Geary N, unpublished data).

Fig. 16.

Sex and the density of fungiform papillae (FP) on the tongue interact to determine human hedonic responses to sweet-creamy flavor mixtures. Combinations of sugar solutions and cream were rated using the general labeled-magnitude-estimation scale, which enables valid comparisons of measurements of subjective experience between groups (e.g., between sexes). Men and women with low and high FP densities were analyzed separately. The x-axes are the sensory intensities (i.e., not hedonic intensities) of the sweetness of the stimuli, and the y-axes are the sensory intensities of their creaminess (0 = no sensation; 100 = the strongest imaginable sensation of any kind); note that the sensory intensities of the stimuli tested ranged from 0 to 90. The pleasantness of the stimuli (−100 = strongest imaginable disliking, 0 = neutral; 100 = strongest imaginable liking) are displayed as isohedonic contours; that is, each line indicates the various sweet-creamy combinations that were judged to have a particular pleasantness, the values of which are given on the contours. Insets on the graphs indicate the range of intensities of pleasantness observed. For example, men who had low FP density found the hedonic intensity of the stimuli to range from approximately −5 to ∼20, with maximum liking (smallest contour area) for stimuli with sensory intensity ∼50 sweet and ∼50 creamy. Note that men with low FP densities and women with high FP densities liked best intermediate sweet-creamy intensities best (maximum liking for men, ∼50 sweet, ∼50 creamy and for women, ∼30 sweet, and ∼40 creamy), but that their degrees of liking were moderate (<25 for men, <20 for women). In contrast, men with high FP densities and women with low FP densities liked higher sweet-creamy intensities best (90 sweet, 90 creamy were most liked by both sexes) and endorsed higher degrees of liking (>30 for men, >40 for women). Note also that flavor mixtures that women with low FP densities liked most (upper right part of graph) were disliked by women with high FP densities. Reprinted from Physiology and Behavior, Oral sensory phenotype identifies level of sugar and fat required for maximal liking, John E. Hayes and Valerie B. Duffy, 95: 77–87, 2008; republished with permission from Elsevier; from Hayes and Duffy (316).

Fig. 17.

Male-female sex difference in rats' propensities to binge eat. Thirty male and 30 female rats were offered standard chow ad libitum and a palatable commercial cake frosting 3 days/wk for 2 wk, a procedure that leads to increased palatable food intake in comparison to ad libitum access to the same food (138, 139). Four-hour palatable food intakes in each of the six tests were ranked across all rats, and individual differences in binge-eating propensity were scored. Data are percentages of male and female rats that were binge-eating prone (i.e., scored in the highest tertile of palatable food intake in 3 or more of the 6 tests and never scored in the lowest tertile) or binge-eating resistant (i.e., scored in the lowest tertile of palatable food intake in three or more of the six tests and never scored in the lowest tertile). *Significant sex difference, two-proportion z test, P < 0.001. Adapted from International Journal of Eating Disorders, Sex differences in binge eating patterns in male and female adult rats, Kelly L. Klump, Sarah Racine, Britny Hildebrandt, and Cheryl L. Sisk, 95: 77–87, 2008; republished with permission from John Wiley and Sons; from Klump et al. (396).

Fig. 18.

Estradiol-treated ovariectomized rats (RYGB-E2) eat less (B) and gain less weight (A) after Roux-en-Y gastric-bypass surgery (RYGB) than untreated ovariectomized rats (RYGB-OIL), and these effects of estradiol were similar to those in rats with sham RYGB surgeries (SHAM-E2 and SHAM-OIL). Rats were fed solid, high-energy diet for 3 wk preoperatively (phase 1) and for 4 wk postoperatively (phase 2); they were then fed Ensure Plus liquid diet for 3 wk (phase 3). #SHAM-OIL significantly different from RYGB-OIL; *RYGB-OIL significantly different from RYGB-E2; +SHAM-OIL significantly different from RYGB-E2, all P < 0.05. Reprinted from Gastroenterology, Estradiol increases body weight loss and gut-peptide satiation after Roux-en-Y gastric bypass in ovariectomized rats, Lori Asarian, Kathrin Abegg, Nori Geary, Marc Schiesser, Thomas A. Lutz, and Marco Bueter, 143: 325–327.e2, 2012; republished with permission from Elsevier; from Asarian et al. (13).

Fig. 19.

Schematic summary of the activational effects of gonadal steroid hormones on eating, emphasizing hypothesized neural mechanisms and their integration. The diagram is based on our review of rat, mouse, and anthropoid primate, including human, data. It is superimposed on a schematic midsagittal section of a rat brain, although most named structures are lateral to the midline. Red arrows and text boxes indicate estrogenic mechanisms; question marks and black font identify less well-established mechanisms. Estrogens acting on ERα on neurons in the cmNTS (filled oval) affect the neural processing of peripheral CCK signals (solid red arrow) so as to reduce meal size, food intake, and body weight; the same ERα neurons are hypothesized to be involved in the processing of a variety of other peripheral signals, especially ghrelin and gustatory signals, which are apparently affected by estrogens (dashed red arrows). ERα in the dorsal raphe and several hypothalamic areas are not strongly implicated in the control of eating (open red oval). A number of forebrain signaling molecules, especially 5HT and AgRP, as well as flavor hedonics contribute to the estrogenic control of eating, probably via hypothalamic and telencephalic mechanisms (dashed red arrows). Neural processing in these areas is presumably linked bidirectionally to the cmNTS and other brain stem areas (double-headed dashed red arrow), so that cmNTS ERα may also mediate these effects; non-ERα-expressing AgRP neurons in the Arc are the strongest candidates. Androgens acting on AR in unknown sites increase meal frequency, food intake, and body weight (green arrows and text boxes). In contrast, progestins appear not to have physiological effects on eating (blue, dashed text box). Challenges for future mechanistic studies of sex differences in eating include 1) establishing the physiological and pathophysiological roles of the estrogenic mechanisms shown and 2) identifying the androgenic mechanisms affecting eating.