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Plasma concentrations of leptin, insulin-like growth factor-I, and insulin
in relation to changes in body condition score in heifers1
H. V. León*, J. Hernández-Cerón*, D. H. Keisler†, and C. G. Gutierrez*2
*Departamento de Reproducción, Facultad de Medicina Veterinaria, Universidad Nacional Autónoma
de México, Ciudad Universitaria 04510, México and †Department of Animal Science,
University of Missouri, Columbia 65211
ABSTRACT: The objective of this study was to determine the relationships among plasma concentrations
of leptin, insulin, and IGF-I with dynamic changes in
body condition scores (BCS) in heifers. Nineteen ZebuBrown Swiss crossbred heifers, 24 to 30 mo old,
weighing 322 ± 9 kg, and with an initial BCS of 2.6 ±
0.11 (range = 1 to 9) were used. Heifers were fed 60%
of their maintenance requirements until they reached
a BCS of ≤2. Heifers were then maintained at that level
for 25 d, after which they were fed to gain 1 kg of body
weight daily until a BCS of 6 was reached. Heifers were
weighed weekly and BCS was measured every 2 wk.
Plasma samples were collected twice weekly, and leptin
and insulin were determined by RIA. An immunoradiometric assay was used to measure IGF-I from one sample every 2 wk. Plasma concentrations of leptin were
positively correlated during nutritional restriction (NR)
and weight gain (WG) periods with BCS (r = 0.47 for
NR, and r = 0.83 for WG; P < 0.01) and body weight
(r = 0.40 for NR, and r = 0.78 for WG; P < 0.01). Plasma
concentrations of leptin decreased during nutritional
restriction (P < 0.01) as BCS decreased. During weight
gain, leptin concentration increased at BCS 3 and there-
after for each integer change in the BCS. Regression
analysis showed that changes in body weight affect leptin concentrations within a given BCS. There was a
decrease in IGF-I as BCS declined (P < 0.01). During
weight gain, by contrast, IGF-I increased significantly
(P < 0.01) with every unit change in body condition up
to BCS of 4 and plateaued thereafter. Insulin concentrations did not change during nutritional restriction when
BCS decreased from 3 to 1. However, once the diet
was improved, there was a large increase in insulin
concentrations in heifers with BCS 1 (P < 0.01). Among
heifers of BCS 2 and 3, insulin did not differ and was
lower than in heifers of BCS 1 (P < 0.01). Insulin increased (P < 0.01) among heifers at BCS 4 to 6. Leptin
was positively correlated (P < 0.01) with both IGF-I (r =
0.34 for NR, and r = 0.36 for WG) and insulin (r = 0.18
for WG). Insulin was correlated with IGF-I (r =0.60; P
< 0.01). During nutritional restriction, insulin did not
correlate with leptin (r = −0.05), BCS (r = −0.03), or
IGF-I (r = 0.07). It was concluded that leptin serves as
a dynamic indicator of body condition in heifers, as well
as an indicator of nutritional status.
Key Words: Beef Heifers, Insulin, Insulin-Like Growth Factor-I, Leptin, Nutrition
2004 American Society of Animal Science. All rights reserved.
J. Anim. Sci. 2004. 82:445–451
et al., 1994; Halaas et al., 1995). Variations in peripheral concentrations of leptin provide a signal to change
food intake or fat depot mobilization to maintain energy
balance in humans (Isidori et al., 2000; Brann et al.,
2002). In the short term, fasting decreases leptin concentrations (Ahima et al., 1996), whereas refeeding results in an increase in leptin by regulating its synthesis
and secretion in rats (Caro et al., 1996).
In sheep, leptin receptors have been localized in the
hypothalamus and are differentially expressed in hypothalamic regions of well-fed vs. undernourished ewes
(Dyer et al., 1997). In addition, leptin has been found
to be involved in the regulation of food consumption
(Morrison et al., 2001), reproductive function (Nagatani
et al., 2000), and thermoregulation (Mostyn et al.,
Metabolic cues that relate nutritional status to physiological processes within an animal are not fully understood. Leptin is produced by white adipocytes, and circulating concentrations are reportedly correlated with
the amount of fat tissue in humans and rodents (Zhang
This work was supported by Consejo Nacional de Ciencia y Tecnologia (CONACYT), research grant J27756-B; H. V. León was funded
by a CONACYT scholarship. We acknowledge H. Montaldo and C.
Vazquez for their advice in the statistical handling of the data.
Correspondence—phone: 52-55-56225860; fax: 52-55-56167110;
E-mail: [email protected]
Received April 30, 2003.
Accepted October 10, 2003.
León et al.
Table 1. Ingredient composition, daily feed intake, and
nutrient analysis of diets fed to heifers during nutritional
restriction and weight gain periods
Ingredient composition, DM basis
Stargrass hay (Cynodon plectostachyus), %
Soybean meal, %
Corn grain, %
Cane molasses, %
Daily feed intake, kg DM/d
Nutrient analysis
DM, %
CP, %
Ruminally nondegradable protein, %
ME, Mcal/kg
ADF, %
NDF, %
Insulin and IGF-I are also putative mediators of nutritional status (Bossis et al., 2000) and their peripheral
concentrations are positively correlated (McGuirre et
al., 1992). In cattle maintained in a negative energy
balance, insulin and IGF-I are low (Beam and Butler,
1998; Roche et al., 2000). In contrast, well-fed cattle
have elevated concentrations of these hormones (Gutierrez et al., 1997; Bossis et al., 2000).
In cattle, body condition score (BCS) is positively
correlated with abdominal fat as well as with fat stored
within and between muscle tissues (Otto et al., 1991).
However, there are no data on the relationship between
leptin concentrations and BCS and their association
with insulin and IGF-I. Thus, the objective of this study
was to determine the relationship between leptin, insulin, and IGF-I over a wide range of BCS in heifers.
Materials and Methods
Animals and Nutritional Treatments
The study was carried out in the state of Chiapas,
within the dry tropical area of Mexico. It was conducted
from April to November during the drought (April to
May) and rainy periods (June to November). Nineteen
24- to 30-mo-old Zebu × Brown Swiss heifers with a
BCS of 2.6 ± 0.11 (range = 1 to 9; Richards et al., 1986)
were purchased from local producers. Heifers were
transferred to a university facility and adapted to the
management in that facility. Animals were fed 60% of
their maintenance requirements (4 kg DM, 2.4 Mcal/
kg ME, and 7.6% CP; Table 1) to provoke weight loss
until BCS were ≤2 for all heifers. The weight loss period
lasted for 60 ± 14 d. Once the last heifer had reached
the target BCS, the same food allowance was given for
an additional 25 d and no changes in body weight were
observed during this period. Thereafter, heifers were
fed to gain 1 kg of body weight daily until a BCS of 6
was reached (8.2 kg DM, 2.7 Mcal/kg ME, and 10.3% CP;
NRC, 1996). Heifers were fed twice daily and weighed
weekly, and BCS was measured every 2 wk. Only 13
heifers reached BCS 1 by the end of the weight loss
period. At the start of the weight gain period, only three
remained in BCS 1 and the rest were in BCS 2. Thereafter, all heifers went through all scores of increasing
body condition up to BCS 6. Heifers had free access to
water and mineral salts (Ca, 12.8%; P, 18.43%; Mg,
4.88%; NaCl, 2.81%; Mn, 144 ppm; Cu, 365 ppm; Co,
13 ppm; Zn, 1,700 ppm; and S, 37.3 ppm) throughout
the study.
Blood Sampling and Radioimmunoassays
Blood samples (10 mL) were drawn from the jugular
vein of heifers before the first meal of the day, twice
weekly throughout the study. Blood was collected into
prechilled tubes containing 100 ␮L (3.5 mg/mL) of sodium citrate and kept on ice until plasma was harvested
by centrifugation (1,500 × g for 10 min) within an hour.
Plasma was stored at −20°C until assayed.
Plasma concentrations of insulin were determined in
duplicate aliquots of the twice weekly samples via a
solid-phase RIA (Coat-A-Count kit, Diagnostic Products
Corp., Los Angeles, CA) as described by DiCostanzo et
al. (1999). The intra- and interassay CV were 7 and
10%, respectively. Quantification of IGF-I concentrations were performed in duplicate in a single immunoradiometric assay from one sample every 2 wk (DSL-2800
kit, Diagnostic Systems Laboratories Inc., Houston, TX)
with an intraassay CV of 9%. Sample dilution and the
standard curve were found to be parallel. Leptin determinations were made in triplicate using the RIA procedures as described by Delavaud et al. (2000) with intraand interassay CV below 10%.
Statistical Analyses
The effect of BCS on plasma concentrations of leptin,
insulin, and IGF-I for the period of nutritional restriction and weight gain was analyzed by ANOVA for repeated measurements, allowing for variation of BCS
and animal within BCS. Time and weight were completely confounded. Similar BCS were considered separately in the analysis if they were taken during the
nutritional restriction or weight gain periods. The difference in hormone concentrations between BCS was
tested using the animal within BCS as an error term.
For each BCS, at least five samples per heifer were
analyzed for leptin and insulin and one for IGF-I. The
difference between BCS groups was determined by
mean square difference. The existing relationship between body weight and leptin was determined by Pearson correlation (n = 543 paired samples). Similarly, the
relationship between BCS and hormone concentrations
was determined by Spearman correlation (insulin and
leptin, n = 543; IGF-I, n = 125 paired samples).
Daily changes in body weight were calculated by the
difference between consecutive weight measurements.
The values were subjected to third-order regression
Endocrine changes with body condition in heifers
analysis (R2 = 0.29) in a model that included heifer,
day, the quadratic and cubic effects of day, and their
interaction with heifer. The predicted changes in body
weight (PCBW) for each animal were recorded for further analysis.
The relationship between body weight change and
leptin concentration for each score of body condition was
analyzed by regression analysis. Natural logarithmic
transformation of leptin was used to correct for heterogeneity of variance. The model included the BCS (taken
as a continuous variable), PCBW, the quadratic effects
of both, the interaction between BCS and the quadratic
effect of PCBW, and the interaction between quadratic
effect of both BCS and PCBW (R2 = 0.57). All analyses
were conducted using the Statistical Analysis System
(SAS Inst., Inc., Cary, NC).
Average body weight of heifers at the start of the
study was 322 ± 9 kg. After feed restriction, heifers
reached the target BCS (≤ 2) weighing 276 ± 5.5 kg;
having lost approximately 15 to 18% of their initial body
weight in 60 ± 14 d. There was a positive correlation
between plasma concentrations of leptin and BCS during both nutritional restriction (NR) and weight gain
(WG) periods (r = 0.47 for NR, and r = 0.83 for WG; P
< 0.01). Figure 1 illustrates peripheral concentrations
of leptin in heifers during nutritional restriction and
weight gain. Concentrations of leptin differed at each
body condition score when heifers were losing weight
(BCS 3 = 1.53 ± 0.05 ng/mL, BCS 2 = 1.17 ± 0.04 ng/
mL and BCS 1 = 0.69 ± 0.09 ng/mL). During weight gain,
leptin concentrations increased at BCS 3. Thereafter,
leptin concentrations increased for each integer change
in the BCS scale (BCS 1 = 0.69 ± 0.41 ng/mL and BCS
6 = 8.22 ± 0.13 ng/mL). Interestingly, at BCS 3, leptin
concentration differed (P < 0.01) depending on whether
heifers were losing (1.53 ± 0.05 ng/mL) or gaining
weight (2.15 ± 0.07 ng/mL). Body weight was positively
correlated with leptin (r = 0.40 for NR) although the
correlation was stronger during weight gain (r = 0.78).
The relationship between peripheral concentrations
of IGF-I and BCS is shown in Figure 1. There was a
decrease (P < 0.01) in IGF-I concentrations as BCS
declined. By contrast, during weight gain IGF-I increased (P < 0.01) with every unit change in body condition up to BCS of 4 and plateaued thereafter. Insulin
concentrations did not change during nutritional restriction between BCS 3 and 1. After the diet was improved, there was a large increase in insulin concentrations in heifers with BCS 1 (P < 0.01). Among heifers
in BCS 2 and 3, insulin did not differ and was lower
than that found in heifers in BCS 1 (P < 0.01). Insulin
increased (P < 0.01) again among heifers in BCS 4 and
again in heifers at BCS 6 (Figure 1). During the weight
gain period, there was a positive correlation between
BCS with insulin (r = 0.25; P < 0.01) and IGF-I (r = 0.40;
P < 0.01). In addition, leptin was positively correlated (P
Figure 1. Concentrations of leptin (top panel), IGF-I
(middle panel), and insulin (bottom panel) in heifers as
related to body condition score during the period of nutritional restriction (NR) and weight gain (WG). Within hormone, means represented by bars bearing different letters,
differ (P < 0.05).
León et al.
Figure 2. Relationship between predicted changes in body weight (PCBW), body condition score (BCS), and leptin
concentrations for heifers during the period of nutritional restriction (NR) and weight gain (WG). The response surface
was calculated by regression analysis where log leptin = −0.06BCS + 0.16PCBW + 0.09BCS2 + 0.12PCBW2 + 0.045(BCS
× PCBW2) − 0.015 (BCS2 × PCBW2); R2 = 0.57.
< 0.01) with both IGF-I (r = 0.34 for NR, and r = 0.36
for WG) and insulin (r = 0.18 for WG). Insulin was
correlated with IGF-I (r =0.60; P < 0.01). During nutritional restriction, conversely, insulin did not correlate
with leptin (r = −0.05), BCS (r = −0.03) or IGF-I (r =
0.07). Positive correlations were also found between
body weight and BCS (r = 0.60 for NR, and r = 0.86 for
WG; P < 0.01).
The relationship between predicted changes in body
weight, body condition score, and leptin concentrations
among heifers during the period of nutritional restriction and weight gain is shown in Figure 2. It was observed that PCBW affected leptin concentration within
a given BCS (i.e., at a given BCS, a more positive change
in body weight results in higher peripheral concentrations of leptin). The quadratic effect of PCBW and its
interaction with BCS was significant, thus indicating
that the change in leptin concentration varied depending on the BCS exhibited by the heifer.
The results of this study provide evidence that a positive relationship exists between peripheral concentrations of leptin and body weight, body condition score,
and the metabolic hormones insulin and IGF-I over
nutritional restriction and body weight gain in heifers.
Moreover, not only was there a strong positive correlation between plasma concentrations of leptin with body
weight or BCS, plasma concentrations of leptin differed
for each increment in BCS. Leptin concentrations decreased with the loss of every point in BCS. In contrast,
a 40% increase in leptin concentration was observed
when BCS increased 1 point on the 1-to-9 BCS scale.
Hence, leptin concentrations were over nine times
greater in heifers with a BCS of 6 when compared to
animals with a BCS of 1. Similar increases in leptin
concentrations were reported to occur in sheep as BCS
changed (Delavaud et al., 2000). These data are congru-
Endocrine changes with body condition in heifers
ent with the association reported between the amount
of abdominal and peripheral fat stores and the scale of
body condition (Otto et al., 1991). In addition, in this
study, leptin concentrations within a single BCS were
affected by changes in body weight. Similar results were
reported by Amstaldem et al. (2000, 2002), who observed that acute fasting decreased leptin and abundance of its mRNA without affecting BCS. This effect
of body weight change could explain the observed difference in leptin concentrations between animals that
shared similar BCS but differed in their nutrient intake
(i.e., at a BCS of 3, leptin concentration was 1.53 ± 0.05
ng/mL when heifers were feed-restricted and 2.15 ± 0.07
ng/mL when heifers were gaining weight). Nonetheless,
leptin concentrations in feed-restricted heifers at BCS
3 were greater than those observed in heifers gaining
weight at a BCS of 2. Taken together, these results
provide evidence that leptin concentrations vary with
BCS changes and that peripheral concentrations of leptin could be an objective indicator of nutritional status
in cattle.
It is anticipated that the increase in peripheral concentrations of leptin was due to an increase in fat deposits, given that it was described that leptin expression
is up-regulated as fat stores increase (Thomas et al.,
2002) and down-regulated when negative energy balance and lipolysis occur (Kadokawa et al., 2000; Sansinanea et al., 2001). Furthermore, the leptin concentrations reported herein are within the range of those values reported to exist in dairy and beef cattle (Block et
al., 2001; Delavaud et al., 2002). However, it should be
noted that for cows of similar BCS (around 3.5), leptin
concentrations in Charolais cattle were 6.6 ng/mL,
whereas, in Holstein cattle, concentrations were twice
as high (13.7 ng/mL) (Delavaud et al., 2002). In addition, plasma concentrations of leptin may vary according to the characteristics of fat deposition between
breeds. Indeed, in sheep (Chilliard et al., 2001) and
humans (Ahima and Flier, 2000), it was reported that
abdominal fat has lower abundance of leptin mRNA
than does peripheral or subcutaneous fat. Recent results reported for the bovine indicate that there was a
greater abundance of leptin mRNA in Japanese Black
steers compared to their Holstein counterparts (Higashiyama et al., 2003). Thus, differences in the distribution of fat stores between breeds may be reflected in
the amount of leptin they produce.
Peripheral concentrations of insulin did not differ
among BCS in heifers during nutritional restriction,
perhaps due to low glucose and/or propionic acid availability in these animals (Herdt, 2000). However, when
heifers were fed to gain weight in the current study,
there was a twofold increase in insulin (Figure 1) that
represented a greater concentration than observed in
heifers in BCS 2 and 3. This acute rise in peripheral
concentrations of insulin has been observed in animals
after a period of feed restriction (Ford and Parks, 2000)
and could represent a signal for the initiation of the
anabolic process in compensatory growth (Hornick et
al., 2000). When BCS increased to 4 and then again
from 5 to 6, there occurred another significant increased
in insulin. An association was reported between mass
of fat tissue depots and augmented insulin concentrations or with resistance to the action of insulin (Poretsky et al., 1999). Perhaps our heifers presented some
degree of insulin resistance once they started accumulating fat tissue. Indeed, Herdt (2000) and Kushibiki
et al. (2001) reported that cattle with high BCS present
hyperglycemia, hyperinsulinemia, and insulin resistance, similar to the symptoms of diabetes mellitus type
II. In addition, it was reported recently that fat tissue
produces resistin, a protein whose secretion is up-regulated with increased adiposity and that causes insulin
resistance (Steppan et al., 2001).
As expected, IGF-I increased when BCS of the heifers
improved. A positive correlation among IGF-I, insulin,
and BCS was reported previously in heifers and beef
cows (Bishop et al., 1994; Vizcarra et al., 1998). However, in the present study, as heifers achieved a higher
BCS, the rate of increase in insulin and IGF-I differed
(Figure 1). Total circulating IGF-I concentrations increased steadily between BCS 2 to 4 and plateaued
after BCS 4. This may highlight differences in the mechanisms regulating the production of IGF-I and insulin.
The liver produces IGF-I in response to GH stimulation.
Feed restriction of animals provoked a decline in circulating concentrations of IGF-I, despite elevated concentrations of GH (Yambayamba et al., 1996). This lack of
response of the liver is caused by reduced insulin; thus,
IGF-I concentrations are low (McGuire et al., 1992;
Thissen et al., 1994). After adequate food supply is reestablished, IGF-I production increases due to augmented
GH receptor sensitivity in response to the action of
elevated insulin (Pao et al., 1993). Therefore, IGF-I and
insulin are physiologically linked and both increase
with enhanced BCS. However, the regulation of each
hormone individually may vary according to metabolic
status, and the direction of the changes in body weight.
Finally, when animals were gaining weight, a positive correlation between circulating concentrations of
leptin and IGF-I and of leptin and insulin were found.
Thus, insulin, IGF-I, and leptin were positively associated with body weight and BCS. Friedman and Halaas
(1998) reported that plasma concentrations of leptin
were positively correlated with body fat mass and body
weight in humans. In addition, Delavaud et al. (2002)
reported that the size of the adipocyte dictates its content of mRNA for leptin independently of the BCS of the
cow and proposed this to be the major factor regulating
leptin secretion. Houseknecht et al. (2000) reported that
IGF-I mRNA and leptin mRNA abundance were highly
correlated in bovine adipose tissue.
Of general interest, we noted that after nutritional
restriction of the heifers started, there was a rapid decrease in body weight for wk 8. Thereafter, although
the decline in condition continued, the rate of weight
loss decreased dramatically. This pattern has been previously characterized by Rhodes et al. (1996) and Bossis
León et al.
et al. (2000), who reported a fast rate of weight loss
when nutritional restriction started, but animals
seemed to be more resistant to weight loss after some
weeks if feed restriction continued. This apparent adaptation to undernourishment is likely influenced by endocrine mechanisms that control energy expenditure
and preservation of vital functions. In this study, insulin was at its lowest during nutritional restriction regardless of BCS, whereas IGF-I decreased gradually.
Indeed, it was observed that both insulin and IGF-I are
reduced with feed restriction allowing fat mobilization
(Hocquette et al., 1998). If feed restriction is prolonged,
the increase in GH will directly prevent damage of vital
organs by directing energy expenditure to the use of
fat and sparing protein removal (Houseknecht et al.,
1995; Hippen, 2000).
Changes in insulin, IGF-I, and leptin play important
roles in metabolic adaptation of cattle to changes in
weight and body condition. Our observations provide
evidence that assessment of leptin is neither merely a
simple nor a more complex substitute for assessment
of BCS, but that leptin serves to provide a more dynamic
perspective of the nutritional status of the animal in
ways that cannot be scrutinized through the use of
BCS alone.
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