AMER. ZOOL., 16:649-659 (1976).
Circadian Hormone Rhythms in Lipid Regulation
ALBERT H. MEIER AND J O H N T. BURNS
Department of Zoology and Physiology, Louisiana State University, Baton Rouge,
Louisiana 70803
SYNOPSIS Many of the significant events that occur in the life of an animal are regulated
by hormones. Because lipids are the principal energy reserve, it is axiomatic that the regulation of fat synthesis and mobilization would be closely interrelated with the regulation
of physiological and behavioral events. The circadian rhythms of prolactin and the corticosteroid hormones have important roles in regulating daily and seasonal changes in body
fat stores and in organizing the total animal so that metabolism, reproduction, and behavior are fully integrated.
LIPID METABOLISM AND HORMONES
Body fat stores constitute an important
energy reserve in vertebrates. The amount
of fat that is present at any time is the net
effect of deposition and mobilization. The
fat that is deposited in adipose tissue and
other organs such as the liver may be derived from either dietary fat or de novo
synthesis. Both synthesis and mobilization
are processes that are self-regulating to
some extent but many hormones influence
the rates of lipid metabolism and thus the
balance between lipogenesis and lipolysis.
Lipogenesis occurs primarily in the liver
in most vertebrates although it also occurs
to a considerable extent in the adipose tissue in rodents. The triglycerides that are
found in the liver are released into the
blood where they are transported as lipoproteins. The lipoproteins are acted upon
by lipoprotein lipase in the adipose tissue
and the triglycerides are moved into the
adipocytes for storage. Adipose tissue is the
principal storage site for fat in higher vertebrates but considerable storage also occurs in the liver, especially in some lowervertebrate species (Dessauer, 1955; Jonas
and Bilinski, 1964). Mobilization results in
the release of free fatty acid (FFA) in the
blood where it is linked with albumen. The
A. H. Meier is supported by NSF research grant
GB-42690. We thank Ms. Wendie Maas for her assistance in preparing the illustrations and Ms. Christine
Angelloz for typing the manuscript.
FFA is taken up by muscle and liver and degraded by /3-oxidation to acetyl CoA which
may enter the citric acid cycle with the production of ATP. A simplified schematic of
lipid metabolism is provided in Figure 1.
For general reviews, see Goodman (1974),
Numaand Yamashita (1974), and White, et
al. (1964).
The synthetic pathway for the formation
of fatty acids from acetyl CoA differs from
the /3-oxidation pathway. A key step in
lipogenesis is the formation of malonyl
CoA from acetyl CoA and CO 2 . Many
workers believe that this reaction is rate
limiting. Malonyl CoA is committed to become 2-carbon segments of fatty acid
chains with loss of CO2- Triglycerides are
produced from the fatty acids in a series of
reactions that require a supply of a-glycerol
phosphate.
In a brief review it is not possible to provide a complete outline of hormone function in lipid metabolism. It is not possible,
for example, to discuss all of the permissive
and synergistic effects of hormones. Because lipid metabolism is interrelated with
carbohydrate and protein metabolism it is
not even realistic to consider one by itself.
Nevertheless there are some basic mechanisms that can be mentioned.
Because of specific requirements for
coenzy mes and substrates, lipogenesis must
be accompanied by carbohydrate metabolism. Much of the lipogenic influence of
insulin is attributable to its role in carbohydrate metabolism. It promotes the utili-
649
650
ALBERT H. MEIER AND JOHN T. BURNS
Triglycerldes
V
«JI»OS«
tf-glyceroi-P
t
Lipo
FFA-Albu
Glucose
Cluco
Fatty
Trig l y c e n d e s
ironophospha
shunt)
K«
,„„>-,
idat.or.)
Fatty Acids
NADP^
NADPH y
NAO •*.
L
«(-g1ycern 1-P ^
pADM
Male iyl CoA
-^.Acetyl
CoA ^ _
J
C.tr.c ic!d Cycle
FIG. 1. Simplified scheme of lipid metabolism.
geons (Bates, et al., 1962). Obesity resulting
from chronic growth hormone administration is also accompanied by the development of progressive pancreatic islet hypertrophy and hyperplasia indicative of increased insulin production (Mahler and
Szabo, 1971).
Prolactin has been shown to h ave marked
stimulatory influences on body fat stores
(discussed later). However it has received
relatively little attention with regard to possible influences on lipogenesis. In vitro
studies of fish (de Vlaming, personal communication) indicate that prolactin stimulates the rapid formation of hepatic lipids.
Prolactin given in vivo but not in vitro also
stimulates the activities of several enzymes
involved in lipogenesis in the common pigeon, Columba livia (Goodridge and Ball,
1967).
Studies of rat adipose tissue indicate that
prolactin has several lipogenic activities
thatare similar to those of insulin. Provided
that glucose is present, it stimulates the
synthesis of fatty acids in vitro from acetate
or pyruvate and directs carbohydrate
metabolism through the hexose monophosphate shunt (Martin, et al., 1958). On
the other hand, prolactin does not repair
fatty acid synthesis in alloxan-diabetic rats
whereas insulin does (Narahara and
Williams, 1958). Narahara and Williams
suggested that prolactin delays the degradation of insulin thereby increasing its activity.
Hormonal regulation of fat mobilization
centers on the hormone-sensitive lipase
which catalyzes the conversion of triglycerides to fatty acids (Fig. 2). Epineph-
zation of glucose with the formation of
a-glycerol phosphate and accelerates the
conversion of pyruvate to acetyl CoA (Jungas, 1970). Insulin also promotes lipogenesis in adipose tissue by making glucose
available through facilitated transport
(Winegrad and Renold, 1958; Schimmel
and Goodman, 1971).
The coenzyme NADPH is a key requirement for the conversion of malonyl CoA to
fatty acids. Insulin promotes the production of NADPH by directing carbohydrate
metabolism through the hexose monophosphate shunt (Winegrad, et al., 1959).
Glucagon, which has an inhibitory effect on
lipogenesis, has just the opposite effect on
carbohydrate metabolism (Rudack, et al.,
1971). The opposing activities of insulin
and glucagon may be related to their inhibitory and stimulatory effects, respectively, on cyclic AMP. Cyclic AMP inhibits
hepatic lipogenesis as measured by 14C-acetate incorporation in lipids (Akhtar and
Bloxham, 1970; Bricker and Levey, 1972).
In addition to its rapid lipogenic influences, insulin also has a delayed effect by
increasing the synthesis of enzymes involved in lipogenesis (Gellhorn and Benjamin, 1966). Influences on enzyme synthesis may be the basis by which other hormones also influence fat metabolism. Although growth hormone has an immediate
inhibitory effect on fatty acid synthesis in
vitro (Goodman and Schwarz, 1972), administration of the hormone for several
days can repair lipogenesis in hypophysec- FIG. 2. Hormonal effects on fat mobilization in
tomized rats (Nejad, et al., 1962) and pi- adipose tissue.
HORMONES, RHYTHMS, AND FAT STORES
rine, norepinephrine, and glucagon have
strong stimulatory influences on this reaction (Goodman, 1974). ACTH has similar
effects in vitro but it is not clear whether it
has a physiological role. Cyclic AMP also
promotes the conversion of triglycerides to
fatty acids and it is generally accepted that
many of the lipolytic activities of hormones
are consequences of their effects on adenyl
cyclase which catalyzes the conversion of
ATP to cyclic AMP (Robison, et al., 1971).
Thyroxin has a supportive effect on lipolysis, perhaps by way of augmenting catecholamine activity (Goodman and Bray,
1966). Growth hormone and glucocorticoids also have supportive influences
on the mobilization of fat (Raben and
Hollenberg, 1959; Fain and Saperstein,
1970).
Insulin is a potent inhibitor of fat mobilization. It facilitates the movement of glucose into the adipocytes with subsequent
production of a-glycerol phosphate. Thus
when glucose is available most of the fatty
acids mobilized from the triglycerides are
reesterified and little fatty acid is released in
the blood (Crofford and Renold, 1965). Insulin also has an inhibitory influence on the
activity of cyclic AMP, an effect that could
reduce mobilization of fat (Loten and
Sneyd, 1970).
ROLE OF FAT STORES IN SEASONAL AND DAILY
CYCL'ES
Although Iipid metabolism has been
studied intensively in laboratory mammals
and much has been learned concerning the
role of hormones in regulating lipogenesis
and lipolysis, many workers in the field
have concluded that these studies have
generally failed in some important respects. For example, gorging on the one
hand and thinly disguised forms of starvation on the other are still the most effective
ways to gain or lose body weight and fat.
Much is known concerning the individual
parts of the regulatory mechanisms but less
is known about how these mechanisms are
assembled to form a functional, whole animal.
Research in Iipid metabolism seems to
have suffered because of a lack of under-
651
standing of the role of fat stores in the vertebrate system. Considering the economic
and medical incentives for studying Iipid
metabolism, it is not surprising that many
workers view heavy fat stores as manifestations of pathological conditions and gear
their research accordingly. Although heavy
fat stores are pathological in some instances, it is clear from the observations of
many animals in their natural setting that
fat depots have important roles and must
be closely regulated under normal conditions. Because this important subject is
treated in depth elsewhere in this volume
only a few summary remarks concerning
the role of fat stores will be given here.
Heavy stores of body fat have both advantages as well as disadvantages for the
individual. The advantages reside largely
in an efficient means of storing energy. Not
only does fat supply about twice as many
calories as carbohydrates but fat can also be
stored without hydration which is a further
considerable saving in weight and bulk.
These characteristics make fat stores a suitable means of providing energy when it is
needed for the support of physiological,
reproductive, or behavioral events. The
disadvantages of heavy fat stores are probably primarily of an ecological nature
under natural conditions, although they
may also place a heavier burden on the
physiological system. Heavy fat stores tend
to impede locomotion and thus be disadvantageous to both predator and prey. Seasonal fluctuations in body fat stores appear
to be evolutionary adaptations that make
heavy fat stores available when they can
have an adaptive role and eliminate them at
other times.
Seasonal changes in amount of fat stores
are associated with the migratory periods in
birds (Fig. 3). Heavy fat deposits appear
shortly before migration and are maintained throughout the migratory period.
The fat serves as an energy source for sustained flight. An important point to be
noted in this regard is that heavy fat stores
accompany vigorous activity. Thus both
lipogenesis and lipolysis are probably
stimulated during migration. The inverse
relation between locomotor activity and
amount of body fat that is often assumed
652
ALBERT H. MEIER AND JOHN T. BURNS
tions. Instead they indicate that fat stores
are closely regulated and integrated with
the behavioral activities of the animal. The
timing of changes in fat stores seasonally
and daily indicate that the mechanism is
responsive to environmental cues. These
findings indicate that neuroendocrine
mechanisms are involved. Daily variations
in lipogenesis further indicate that
lipogenic hormones must be present in
greater quantities at certain times of day, or
that hepatic cells must be more responsive
at certain times, or both.
J F
FIG. 3. Annual cycle of fat stores in the migratory
white-throated sparrow.
for humans does not even superficially exist
in migrants.
Seasonal changes in fat stores are also
associated with overwintering as in hibernating mammals and in ectotherms such as
the green anole lizard, Anolis carolinensis,
which are dormant through much of the
winter. In the anole, fat is deposited in late
summer and early fall. It is used up slowly
during the winter when the lizard is inactive
and unable to secure food. Thus in contradistinction to a migratory bird, the utilization of fat stores is not associated with
intense locomotor activity.
Seasonal changes in body fat stores are
obviously the cumulative effects of
lipogenesis and lipolysis that occur on a
daily basis. Hepatic lipogenesis appears to
peak during the latter half of the normal
active period in fish (Victor de Vlaming,
personal communication; Meier, unpublished: Fig. 4) and in birds (Roy Martin,
personal communication; Meier, unpublished). Although the daily rhythm of
lipogenesis appears to follow the rhythm of
food consumption, the rhythm of
lipogenesis persists in starved fish (Fundulus grandis) (Meier, unpublished). Thus
lipogenesis may well be augmented by increased food consumption but it does not
depend on it in a fish.
Studies of animals such as migratory
birds have clearly demonstrated that the
major changes in fat stores are adaptive
changes in metabolism not directly related
to food availability under normal condi-
TEMPORAL SYNERGISMS OF CIRCADIAN HORMONE
RHYTHMS IN FAT REGULATION
During the previous decade it has been
demonstrated that many hormones are released in greater quantities at specific times
of day. Our laboratory has been interested
in the function of these daily, or circadian,
rhythms especially with respect to prolactin
and the adrenal corticosteroids. We attempted to simulate endogenous hormone
rhythms by daily injections at specific times
in order to test for possible cumulative responses. Daily injections of prolactin elicited marked changes in amount of body
fat stores in the white-throated sparrow,
Zonotrichia albicolhs, but the effect varied
with the time of day when the injections
were made made (Meier and Davis, 1967).
Daily injections at midday of 16-hour daily
SE
t
I *
-<
\
•
X
\
1400
Time of Day
FIG. 4. Daily rhythm of hepatic lipogenesis in the Gulf
killifish, Fundulus grandis. 3H-acetate was injected 4
hours before the fish were killed for analysis of labelled lipids (unpublished).
653
HORMONES, RHYTHMS, AND FAT STORES
photoperiods promoted large increases in
fat stores approximating the levels observed during the migratory seasons
whereas injections given early in the
photoperiod caused losses in body fat.
Since the initial finding in the whitethroated sparrow, our laboratory has demonstrated daily variations in fattening responses to prolactin in other species including teleost fishes, amphibians, reptiles,
birds, and mammals. Two other laboratories have reported similar findings in
several teleosts (see Table 1 for references).
In addition to the fattening responses
to ovine prolactin, fish show similar responses to fish prolactin preparations
(Victor de Vlaming, personal communication) and the white-throated sparrow is responsive to chicken prolactin (Meier, unpublished). We know of no failure to demonstrate a daily variation in fattening response to prolactin when sufficient times
were tested. The changes in fat stores after
less than a week of daily injections are usually dramatic (see Fig. 5).
The daily rhythm of fattening response
to prolactin is entrained by the daily photoFat (%dry B.W
Midday Inactions
• Controls
• Prolactin
^-~"
56±1
•
<S
8 =
O
•
O
43 + 2
45 ± 1
D
lg+2
D
^ ^
Early Inactions
0 Controls
• Prolactin
Days
FIG. 5. Daily variations in body weight and fat responses to daily prolactin injections in Fundulus
chrysotus. From Lee and Meier (1967).
TABLE 1. Daily rhythms of fattening responses to prolactin entrained by a daily photoperiod or daily injections of
corticosteroids.
Class
Species
Osteichthyes
Photoperiod
Corticosteroid
Fundulus chrysotus
X
X
Osteichthyes
Fundulus grandis
X
X
Osteichthyes
Fundulus kansae
X
Osteichthyes
Fundulus similis
X
Osteichthyes
Cyprinodon vanegatus
X
Osteichthyes
Notemtgonus chrysoleucas
X
Amphibia
Reptilia
Rana pipiens
Anolis carolinensis
X
X
X
Reptilia
Aves
Xanlusia henshawi
Zonotnchia albicolhs
X
X
X
X
Aves
Columba hvia
X
Aves
Mammalia
Coturnix c.japonica
Mus musculus
X
X
Mammalia
Mesocricetus auralus
X
Reference
Lee and Meier, 1967;
Meier, 1969; Joseph and
Meier, unpublished
Joseph and Meier, 1971;
Meier, Trobec, Joseph,
and John, 1971
Mehrle and Fleming,
1970
de Vlaming and Sage,
l1 Q79
U 1 i.
de Vlaming and Sage,
1972
Pardo and de Vlaming,
personal communication;
Meier, 1969
Meier, 1969; Meier,
Trobec, Joseph, and John,
1971
Trobec, 1974
Meier and Davis, 1967,
Meier and Martin, 1971;
Meier, Martin, and
MacGregor, 1971
Meier, Trobec, Joseph,
and John, 1971
Meier, unpublished
Joseph and Meier,
unpublished
Joseph and Meier, 1974
654
ALBERT H. MEIER AND JOHN T. BURNS
Prolactin Release
a>
c
o
-
4
CO
co
co . _
co
olD
••
>
°~ "~ H 1
CO
00
—
CXO
. 2 aS
S "2 —
—
°
^
co
o
*
,— "^^^
•<--
CI
a>
t—>
a> 1—1
C3
CO
X
• 2--S
E
8
a> . E co
— co
,-,
150
cu
CO
0
co
a>
O
—. _
CU
t=
, .
co
CO
^100
0
<->
CO
0
1200
0600
1800
Time of Day
FIG. 6. Temporal relations of fattening responses to
prolactin with hepatic lipogenesis and pituitary prolactin content in white-throated sparrows with heavy
stores of body fat. From Meier (1969), Meier, el al.
(1969), and Meier (unpublished),
HORMONES, RHYTHMS, AND FAT STORES
period. Shifts in the L:D schedule resulted
in appropriate changes in phase of the fattening response rhythm in the Gulf killfish,
Fundulus grandis (Joseph and Meier, 1971).
In addition, the peak of fattening response
occurred 8 hr after the onset of light on 8-,
12-, and 16-hr daily photoperiods indicating that the onset of the daily photoperiod
is the principal entrainer of the fattening
response rhythm in F. grandis.
In the white-throated sparrow, Zonotrichia albicollis, pituitary prolactin is released late in the daily photoperiod in fat
birds but early in the photoperiod or late in
the dark in lean birds (Meier, et al., 1969).
Hepatic lipogenesis (incorporation of 3Hacetate in lipids) peaks late in the photoperiod as expected in fat birds (see Fig. 6).
In addition, prolactin injections cause fattening when given late in the day and loss of
fat stores when given early (Meier and
Davis, 1967; Meier, 1969).
The photoperiodic entrainment appears
to be mediated by the adrenal corticosteroids inasmuch as daily injections of corticosteroids can entrain daily rhythms of
fattening response to prolactin in animals
maintained in continuous light (see Table 1
for references). In most instances the response rhythm is unimodal; but in the
655
white-throated sparrow there are two peaks
of fattening response, one about 4 hr after
the injection of corticosterone and another
about 12 hr afterward (Fig. 7).
After a daily rhythm of fattening response to prolactin has been induced by
corticosteroid injections in Fundulus grandis, the rhythm persists for at least several
days without further injections (Meier, et
al., 197 la). This finding has several possible
interpretations. Because circadian rhythms
apparently have a cellular basis, the corticosteroids may direcdy set daily rhythms
of fattening responses to prolactin in hepatic cells involved in lipogenesis. The cellular
rhythms may persist synchronously for
several days without additional hormonal
entrainment. Alternatively, or simultaneously, the injections of corticosteroid may
set the neuroendocrine system so that the
endogenous rhythm of corticosteroid
would continue to drive a daily rhythm of
fattening response in the same phase as that
produced by daily injections. A possible direct influence by the corticosteroids at the
cellular level is supported by the finding
that corticosterone can directly set at the
tissue level daily rhythms of sensitivity to
prolactin in the pigeon cropsac (Meier, et
al., 19716). Important questions are involved in the corticosteroid-entrained
rhythms of fattening response to prolactin
and further experimental work is needed.
The maintenance of the circadian fattening response to prolactin seems to depend
on adequate amounts of thyroid hormone.
The rhythm of fattening response disappears after 2 weeks in common pigeons,
Columba livia, maintained on continuous
light (Meier, et al., 1971a;John,^o/., 1972).
Treatment with thyroid hormones, how"8
ever, prevents the dampening out of the
rhythm. Apparently the thyroid hormones
are necessary to permit a rhy th m of plasma
corticosteroids inasmuch as the corticosteroid rhythm also dampens out after 2
0
4
8
12
16
20
weeks in pigeons kept on continuous light
(Joseph and Meier, 1973). Corticosterone
PrOISCtin (Hours after corticosterone injection time)
FIG. 7. Temporal relations of corticosterone and pro- entrains the rhythm of fattening response
lactin injections controlling fat stores in the white- in pigeons (John, et al., 1972).
throated sparrow. Daily injections of the hormones
The organismal role of circadian horwere made for 5 days. The mean body fat store for
untreated birds was 20.5% dry body weight. Taken mone rhythms is better understood in some
from Meier and Martin (1971).
respects. Numerous experiments involving
CD
ALBERT H. MEIER AND JOHN T. BURNS
sonal cycles, we have had to make these
studies with several representative species
that have seasonal cycles. The circadian
rhythms of plasma corticosteroids change
greatly in amplitude and phase with respect
to the photoperiod during the course of the
year in the white-throated sparrow Zonotrichia albicollis (Dusseau and Meier, 1971)
and in the green anole, Anolis carolinesnis
(Trobec, 1974). In addition, the corticosterone rhythm changes progressively in the
white-throated sparrow even when the.
birds are kept on a 16-hr daily photoperiod
for 6 months (Meier and Fivizzani, 1975).
The latter results are consistent with the
finding that the white-throated sparrow,
much like other birds, undergoes seasonal
reproductive, metabolic and behavioral
changes under constant environmental
conditions.
Studies of prolactin have also demonstrated seasonal changes in the circadian
rhythm. The time of release of pituitary prolactin varies in May (vernal migratory period) and August (summer photorefractory period) in the white-throated sparrow, Zonotrichia albicollis (Meier, et al.,
1969). Similarly the phase and pattern of
the circadian rhythm of plasma prolactin
varies at 3 different times of year in the
white mullet, Mugis cephalus (Spieler, 1975:
Fig. 8). The seasonal alterations of the
[erence)
injections of prolactin and corticosterone
have demonstrated that the temporal relations between these hormones can induce a
large number of cumulative conditions including some involved in growth, reproduction, metamorphosis, and migration
(reviews, Meier, 1972, 1975; Meier and
MacGregor, 1972). Because of the large
number of tissues and activities that are
affected by these hormones, these results
are not without possible explanation. Of
special significance, though, is the relationship of the conditions produced by each
temporal pattern of hormone injection.
The studies of the migratory whitethroated sparrow are most informative.
Daily injections of prolactin given 12 hr
after daily injections of corticosterone elicit
conditions found during the spring migratory period (heavy fat stores, nocturnal
migratory restlessness oriented northward,
and reproductive stimulation); prolactin injections given 8 hr after corticosterone injections elicit conditions found during the
summer (low levels of body fat, no migratory activity and reproductive inhibition);
and prolactin given 4 hr after corticosterone
elicits fall conditions (heavy fat stores and
nocturnal migratory restlessness that is
oriented southward). (See Meier, et al.,
1971c; Meier and MacGregor, 1972;
Martin and Meier, 1973; Meier, 1975).
These results are significant from several
perspectives. For example they illustrate
the relation of fat metabolism to other
metabolic and behavioral activities in the
organism and they demonstrate the manner in which these activities may be organized by circadian hormone relations for
the production of seasonal cycles that involve many progressive and cumulative
changes.
A role for circadian hormone rhythms in
controlling seasonal conditions demands
that there be not only circadian rhythms of
specific endogenous hormones (corticosteroids and prolactin) but also that the
phases of one or both of the hormone
rhythms must change seasonally so that the
temporal relations between the hormone
rhythms are altered. Because most studies
have been made with mature laboratory
mammals which do not have obvious sea-
200
Y
at
a<
E
150
ra
c
1
\
\
\
SE-
\
•
/
/
o—
1
\
100
\l
i
\
E
ol
»
_____—<
Hroli
656
1
\J
W
?
£Ec7
ad
Time of Day
FIG. 8. Daily rhythms of serum prolactin concentration at 2 seasons in the white mullet, Mugis cephalus.
From Spieler and Meier, Gen. Com p. Endocrinol. (in
press).
HORMONES, RHYTHMS, AND FAT STORES
hormone rhythms are particularly informative in the white-throated sparrow in
that the interval between the daily rise of
plasma corticosterone (equivalent to time
of daily injection of corticosterone) and the
daily release of pituitary prolactin (equivalent to time of daily injection of prolactin) is
about 12 hr in fat birds during the spring
migratory period and about 6 hr in lean
birds during the summer photorefractory period. Thus the studies of endogenous hormone rhythms support the concept
that changes in the temporal relations of
corticosterone and prolactin control seasonal conditions that include amounts of fat
stores.
Because both prolactin and the corticosteroids are caused to be released by many
environmental and physiological stimuli,
such as various stressors (Haus and Halberg, 1962; Horrobin, 1973), one might
expect that these stimuli repeated daily may
be able to influence lipid metabolism. One
study has tested whether the stress of handling performed daily could influence fat
stores (Meier, et al., 1973). When the disturbances (such as that caused by an injection) are repeated for at least 10 days, difference in body fat stores were observed in
fish, lizards, birds, and mammals. After 10
days the amount of body fat varied dramatically in the green ano\e,Anolis carohnensis.
Disturbances at one time of day greatly depressed body fat whereas disturbances at
another time were ineffective or even increased fat stores. Further studies of this
order hold promise in understanding how
behavior may influence fat metabolism.
CONCLUSION
Time is an important dimension in fat
storage and metabolism. There are marked
seasonal and daily variations in lipid
metabolism and body fat. These cycles are
controlled by the circadian rhythms of corticosteroids and prolactin. Prolactin stimulates increases or decreases in fat storage
depending on whether it is present in
larger quantities during daily intervals of
lipogenic or lipolytic sensitivities. The intervals of sensitivity are entrained by the
657
daily photoperiod and mediated by the adrenal corticosteroids. Thus the temporal
synergism of the circadian rhythms of corticosteroid and prolactin hormones involve
a relation between sensitivity rhythms of
cells involved in lipid metabolism and
rhythms of the stimulatory hormone, prolactin. The cumulative effects of various
temporal hormonal patterns account for
the seasonal changes in fat stores.
The temporal synergism of corticosteroids and prolactin controls many other
physiologic, reproductive, and behavioral
conditions. As in the regulation of fat
stores, the circadian rhythms of corticosteroids appear to entrain circadian rhythms
of tissue responses to prolactin that vary in
a circadian manner. Alterations in the
phase relations of the circadian rhythms of
corticosteroids and prolactin produce
many changes in the behavior and metabolism of the organism. This system provides
organization for the total animal and provides it with an appropriate energy base for
different activities.
The temporal horir>onal synergism may
be influenced by various experiences, for
example stress. The repetition of these experiences at specific times of day may be
expected to alter the hormonal relations
and change fat metabolism. Understanding
these temporal effects could lead to simple
ways of regulating fat stores.
Many of the studies involving fat stores
have been made with the assumption that
large stores are consequences of metabolic
and behavioral disturbances which can be
understood and "cured" by biochemical research on the one hand or mental adjustment on the other. Fewer studies have considered the important roles that fat stores
have in the normal animal. These three approaches are largely separate from one
another and some of the researchers often
appear to be proud of their ignorance concerning the other areas. Those who are interested in understanding liporegulatory
mechanisms cannot afford the luxury of
specialization because these mechanisms
are interconnected with phenomena familiar to each of the three disciplines noted
above.
The neuroendocrine mechanism is the
658
ALBERT H. MEIER ANDJOHN T. BURNS
common denominator that integrates the
organism with its external environment
and organizes the internal environment. It
is now clear as well that the circadian
rhythms of hormones are the principal
units in the temporal organization of the
organism. In this context, the control of
body fat stores can only be fully understood
in terms of its relations to the total animal.
(eds.), Handbook of physiology, pp. 211-231. Williams
and Wilkins Co., Baltimore, Md.
Goodridge, A. G. and E. G. Ball. 1967. The effect of
prolactin on lipogenesis in the pigeon: In vivo
studies. Biochemistry 6:1676-1682.
Haus, E. and F. Halberg. 1962. Der circadian adrenalzyklus und seine Bedeuting fur die Reaktionsbereitschaft der Nebennierenrinde Wein
Ztschr. f. inn. Med. 8:361-370.
Horrobin, D. G. 1973. Prolactin: Physiology and clinical
significance. Medical and Technical Publishing, St.
Leonardgate, Lancaster, Pa.
John, T. M., A. H. Meier, and E. E. Bryant. 1972.
Thyroid hormones and the circadian rhythms of fat
and cropsac responses to prolactin in the pigeon.
REFERENCES
Physiol. Zool. 45:34-42.
Akhtar.M.andD. P.Bloxham. 1970. The coordinated Jonas, R. E. E. and E. Bilinski. 1964. Utilization of
lipids by fish. III. Fatty acid oxidation by various
inhibition of protein and lipid biosynthesis 3', 5'tissues from Sockeye salmon (Onchorhynchus nerka).
cyclic monophosphate. Biochem. J. 120:11 P.
J. Fish. Res. Bd. Can. 21:653-656.
Bates, R., R. A. Miller, and M. M. Garrison. 1962.
Evidence in the hypophysectomized pigeon of a Joseph, M. M. and A. H. Meier. 1971. Daily variations
in the fattening response to prolactin in Fundulus
synergism among prolactin, growth hormone,
grandis held on different photoperiods. J.Exp. Zool.
thyroxine and prednisone upon weight of the body,
178:59-62.
digestive tract, kidney, and fat stores. EndocrinolJoseph, M. M. and A. H. Meier. 1973. Daily rhythmsin
ogy 71:345-360.
concentrations of plasma corticosterone in the
Bricker, L. A. and G. S. Levey. 1972. Evidence for
common pigeon, Columba hvia. Gen Comp. Endoregulation of cholesterol and fatty acid synthesis in
crinol. 20:326-330.
liver by cyclic adenosine 3', 5'-monophosphate. J.
Joseph, M. M. and A. H. Meier. 1974. Circadian comBiol. Chem. 247:4914-4915.
ponent in the fattening and reproductive responses
Crofford, O. B. and A. E. Renold. 1965. Glucose upto prolactin in the hamster. Proc. Soc. Exp. Biol.
take by incubated rat adipose tissue: rate limiting
Med. 146:1150-1155.
steps and site of insulin action. J. Biol. Chem.
Jungas, R. L. 1970. Effect of insulin on fatty acid
240:14-21.
synthesis from pyruvate, lactate, or endogenous
Dessauer, H. C. 1955. Seasonal changes in the gross
sources in adipose tissue: Evidence for the hororgan composition of the W/.ard, A nohs Carolinensis.].
monal regulation of pyruvate dehydrogenase. EnExp. Zool. 128:1-12.
docrinology 86:1368-1375.
deVlaming, V. L. and M. Sage, 1972. Diurnal variation
in fattening response to prolactin treatment in two Lee, R. W. and A. H. Meier. 1967. Diurnal variations
of the fattening response to prolactin in the Golden
cyprinodontid fishes, Cyproinodon variegalus and
Topminnow, Fundulus chrysotus. J. Exp. Zool.
Fundulus similis. Marine Sci. 16:59-63.
166:307-316.
Dusseau, J. and A. H. Meier. 1971. Diurnal and seasonal variations of plasma adrenal steroid hormone Loten, E. G. and J. G. T. Sneyd. 1970. An effect of
in the white-throated sparrow Zonvtrichia albicollis. insulin on adipose tissue adenosine 3', 5'-cyclic
monophosphate phosphodiesterase. Biochem. J.
Gen. Comp. Endocrinol. 16:399-408.
120:187-193.
Fain, J. N. and R. Saperstein. 1970. The invohement
of RX A synthesis and cyclic AMP in the activation of Mahler, R. J. and O. Szabo. 1971. Amelioration of
insulin resistance in obese mice. Am. J. Physiol.
fat cell lipolysis by growth hormone and glucocor221:980-983.
ticoids. In B. Jeanrenaud and D. Hepp (eds.), Adipose tissue: Regulation and metabolic functions. Acad. Martin, D. B., A. E. Renold, and Y. M. Dagenais. 1958.
An assay for insulin-like activity using rat adipose
Press, Inc., New York, N.Y.
tissue. Lancet 2:76-77.
Gellhorn, A. and VV. Benjamin. 1966. Fatty acid
biosynthesis and RNA function in fasting, aging, Martin, D. D. and A. H. Meier. 1973. Temporal synerand diabetes. In G Weber (ed.), Advances in enzyme gisms of corticosterone and prolactin in regulating
orientation in the migratory white-throated sparrow
regulation, Vol. 4, pp. 19-41. Pergamon Press, New
(Zonotrkhia albicollis). Condor 75:369-374.
York, X. Y.
Goodman, H. M. 1974. The pancreas and regulation Mehrle, P. M. and W. R Fleming. 1970. The effect of
early or midda) prolactin injection on the lipid conof metabolism. In V. B. Mountcastle (ed.), Medical
tent of Fundulus kansae held on a constant photophysiology. 13th ed., pp. 1776-1807. C. B. Mosby,
period. Comp. Biochem. Physiol. 36:597-603.
St. Louis.
Goodman, H. M.andG. A. Bray. 1966. Role of thyroid Meier, A. H. 1969. Antigonadal effects of prolactin in
the white-throated sparrow, Zonotrichia albicollis.
hormones in lipolysis. Am. J. Physiol. 210:1053Gen Comp. Endocrinol. 13:222-225.
1058.
Goodman, H. M. and J. Schwarz. 1974. Growth hor- Meier, A. H. 1972. Temporal synergism of prolactin
and adrenal steroids. Gen. Comp. Endocrinol.
mone and lipid metabolism in hypothalamoSuppl. 3:499-508.
hypophyseal system. In E. Knobil and W. H. Sawyer
HORMONES, RHYTHMS, AND FAT STORES
659
Meier, A. H. 1975- Chronoendocrinology of verte- Xarahara, H. T. and R. H. Williams. 1958. Effect of
brates. In B. E. Eleftheriou and R. L. Sprott (eds.),
protein added in intro upon insulin degradation and
Hormonal correlates of behavior, pp. 469-549. Plenum glucose uptake by muscle. J. Biol. Chem. 233:1034Press, New York. N.Y.
1040.
Meier, A. H.,J. T. Burns, K. B. Davis, and T. M.John. Nejad, X. S., I G. Chaikoff, and R. Hill. 1962. Hor1971a. Circadian variations in sensitivity of the pimonal repair of defective lipogenesis from glucose in
geon cropsac to prolactin. J. Interdiscipl. Cycle Res.
the liver of the hypophysectomized rat. Endocrinol2:161-171.
ogy 71:107-112.
Meier, A. H.,J. T. Burns, and J. W. Dusseau. 1969. Numa, S. and S. Yamashita. 1974. Regulation of
Seasonal variations in the diurnal rhythms of pituilipogenesis in animal tissues. In B. L. Horecker
tary prolactin content in the white-throated sparand E. R. Stadtman (eds.), Current topics in cellular
row, Zonotnchia albicollis. Gen. Comp. Endocrinol. regulation, Vol. 8, pp. 197-246. Academic Press, New
12:282-289.
York, N.Y.
Meier, A. H. and K. B. Davis. 1967. Diurnal variations Raben, M. S. and C. H. Hollenberg. 1959. Effect of
of the fattening response to prolactin in the whitegrowth hormone on plasma fatty acids. J. Clin. Inthroated sparrow, Zonotrichia albicollis. Gen. Comp. vest. 38:484-488.
Endocrinol. 8:110-114.
Robison, G. A., R. W. Butcher, and E. W. Sutherland
Meier, A. H. and A. J. Fivizzani. 1975. Changes in the
(eds.). 1971. Cyclic AMP. Academic Press, Inc Newdaily rhythm of plasma corticosterone concentration
York, N. Y.
related to seasonal conditions in the white-throated Rudack, D.,B. Davie, andD. Holten. 1971. Regulation
sparrow, Zonotnchia albicollis. Proc. Soc. Exp. Biol. of rat liver glucose 6-phosphate dehydrogenase
Med. 150:356-362.
levels by adenosine 3', 5'-monophosphate. J. Biol.
Meier, A. H., T. M. John, and M. M.Joseph. 19716.
Chem. 246:7823-7824.
Corticosterone and the circadian pigeon cropsac re- Schimmel, R.J.and H. M. Goodman. 1971. Effects of
sponse to prolactin. Comp. Biochem. Physiol.
dibutyril cyclic adenosine 3', 5'-monophosphate on
40:459-466.
glucose transport and metabolism in rat adipose
Meier, A. H. and R. MacGregor III. 1972. Temporal
tissue. Biochim. Biophys. Acta 239:9-15.
organization in avian reproduction. Amer. Zool. Spieler, R. E. 1975. Circadian and seasonal serum
12:257-271.
prolactin levels in some freshwater and estuanne
Meier, A. H. and D. D. Martin. 1971. Temporal synerfishes: Endocrinological, ecological, and mariculgism of corticosterone and prolactin controlling fat
tural implications. Ph.D. Diss., Louisiana State Unistorage in the white-throated sparrow, Zonotrichia versity, Baton Rouge, La.
albicollis. Gen. Comp. Endocrinol. 17:311-318.
Trobec, T. N. 1974. Circadian mechanisms in the horMeier, A. H., D. D. Martin, and R. MacGregor III.
monal control of annual cycles of fat storage and
1971c Temporal synergism of corticosterone and
reproduction in the lizard, Anolis carolmensis. Ph.D.
prolactin controlling gonadal growth in sparrows.
Diss., Louisiana State University, Baton Rouge, La.
Science 173:1240-1242.
White, A., P. Handler, and E.L. Smith. 1964. Principles
Meier, A. H., T. N. Trobec, H. G. Haymaker, R. Macof biochemistry. McGraw-Hill Co., New York, N. Y.
Gregor III, and A. C. Russo. 1973. Daily variations Winegrad, A. I. and A. E. Renold. 1958. Studieson rat
in the effects of handling on fat storage and tesadipose tissue in vitro. I. Effects of insulin on the
ticular weights in several vertebrates. J. Exp. Zool.
metabolism of glucose, pyruvate, and acetate. J. Biol.
184:281-288.
Chem. 233:267-272.
Meier, A. H., T. N. Trobec, M. M. Joseph, and T. M. Winegrad, A. I., W. X. Shaw, F. D. W. Lukens.and W.
John. 1971a1. Temporal synergism of prolactin and
C. Stadie. 1959. Effects of prolactin in vitro of fatty
adrenal steroids in the regulation of fat stores. Proc.
acid synthesis in rat adipose tissue. J. Biol. Chem.
Soc. Exp. Biol. Med. 137:408-415.
234:3111-3114.