hlETABOLIC EFFECTS OF HYPERPIIAGIA IK THE HYPOTHA4LAMIC-HYPERPHA4GIC RAT1*"
K. I.;. J l,ah-<nr\in J . R. B~-a,a.or\r~ 1) rpar t~zen t of iPhy.siology, lTaziaersity of Wesfern Onfario, Londslz, Ontario
Iieceived 1)ecenlbcr 14, 1965
Abstract lletabolic effect> of hyperphagia have been investigated i l l inale rats in which
h3perphagia ~3~ induced by bilateral, electrolytic Iehions in the regisla of the ventromedi;iI nuclei of the hp pothalamu>. I11 the early dynamic phase of hyper- phagia, it \vould appear that increased body weight gain is a direct effect of ancreased energy intake not balanced by the observed increased spoiltaileoais activity. 111 these ;ulilnals increased lipogea~esis (14C-acetate and lC-glucose) and decreased lipoIysis ill vitrs were evident with no evidence of altered thyroid function. Further, as deterlnirled by "S incorporation in costal cartilage, &he hyperphzagia did 11st elicit an increased rate of skeletal growth. Irk the static pha.;e, spontril-neouq activity was not increased, ~raetabolic patterns were signi- ficantly altered in the direction of illcreased lipogenesis and decreased lipolysis, llnd there appeared to be a decreased uptake and release of 131T by the thyroid, which is suggestive of thyroid hypofunction.
Introduction tIyperphagi;i is known to occur after bilateral electrolytic lesions are 111acle
in the hypothalamus, particularly in the region of tbc ventromedial nuclei (1-3). Two distinct phases have been described during the course of hypo- thktlainic hj~perphagia: the 'dynaillic phase' i~nia~eciiately after operation, in which the animal has a two- to three-fold increase in food intake and r;ipidly gains weight; and the 'static ~~laase' in n-hic-h the animal's food intake decreases, :tlthough reirlaininag above that of the controls, and a body weight greatly exceeding that of the conltrois is anaintieincd (4, 5). These hypothalalnic anirraals &re in positive erncrgy h~ilanc-e (6) Isecctuse of the hypcrphagia and, perhaps, hec.:~use of a reduced activity. They consume a large allcal, filling the stomach, anti then sleep alaatil able to eat again (4). This periodic overflow of foot!, or rneal eating, c.ouId conceiva1)ly alter metabolic patterns as has been s%aon-aa in :animals trained to bc nneal eaters (7). ICiahaaaccd lipogenesis has heen dernon- slra tcd in the liver of lnypot halan~ic-hyper~~hagic inice (8) and in the adipose tissue of rats trained to eat their daily ration in a single meal (9, 10). Although fat- deposition is increased in hyperpllagic animals, in the fed state the turnover and rnobilizcktiona of fat in ~alice nlade hypcrp%.aagic by aurotl~iogl~~cose treatment have been found to be decreased ( I 1).
In view of these observatioals, the present experi~nents were perfornled to
This \vork was supported by a grant frorn the Medical Keedrch Council of Canada. "'Faken fronl a t h i s presented by K. M. May to the 1;aculty of (;r,lduate Studies, Tlniversity
of *\Vestern Oaltrarin, in partial fulfill~nent of the requirements for the llegree of Master of Scaence.
T~olornbo I;ellow. Present addresb: 1)epartment of 13hysioL,gy, Medical School, hlandalay, H~iriraa.
Ahfed ical Research Alswciate of the Wledical Icesearch Council of C;lnada.
('anaclian J:brlr~~al of P1lysi:)logy and I'har~nacology. Volume I4 (19ii(;)
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64'2 CANADIAN JOURNAL OF PPIYSIBLOGY AND f'I1XRMA.VO~Gk'. VOL. 44, 19fiii
investigate (a ) energy expenditure, viz. work done, total heat production, and tissue synthesis, by measuring spontaneous activity, total nletabolism, and body weight rcspeetively, a~ad (b) the rraanner in \vhich these ani~nals ha~adle foodstuffs, i.e. their intermediary n-raetabolism with respect to carbohydrate an(% fat.
Experimental and Results ?adult rlinle rats of the 6Vistar strain, with an iiaitiaI body weight of about
200 g each were used throughout this experimental work. The a~ai~alals were fed a synthetic high-carbohydrate diet (30y0 casein, 6475 sucrose, BOYo ooraa oil, 4(z8 salts, 2y0 alphacel, by weight; caloric value 4.1/g) ad libitum. The diet coratained vitttnlins, choline, and in~ositol in quantity adequate for optilnal grc,\\-~h of rats. In one experi~iient, potassius-aa iodide was excluded from the salt nlixtrrre (iodine-free diet). Ilri~nking water was ~ ~ l w a y s available and tlic ~irai~nals nere housed in an e~lviron~nental teaa-aperature of 2-2 & 1 'C: with 12 hours c4f light anel 12 hours of darkness. They were nlaintained in individu;rl ivire mesh cages except during the ~a~easurernneiit of spontaaleous activity w1ae1-i each rat- u7as placed in a revolving-drum activity cage (1-9 iraclnes in diameter) tattac-hed to a stationary living conzpartment. 'The revolutions of the ctrunl 111adc 1) ) - the n~oveinent of the rat were recorded on ;a cour-rter as a naeasure of' spont,ll.ae.ous activity. k'nder pentob;~rbital sodiurna anesthesia (3 nlg/100 g body weight) given intraperitoneally, hyperphagia was induced by bilxteral electrolytic ablation of the ventro~rledial region of the lzypot1aalarnus (2 naa for 15 seconds) with the use of a BIc~rsley-Clarke stercotaxic instrut-nent (I?). Tlae coordinates used for placing the electrode were arikerior 6 111111, vertical 3.6 mni, and lateral 1 Inm. Location of the lesions was confirrilcd histologic-ally at autopsy.
Food Putnke, Pieeding Pattern, (end Body Weight Chin 'Fhe average daily food intake of imiile hy~~othala~nic-hyperphagic anti tlne
snnie number sf control rats was determined from postoperative day 7 to day 30 (dl ~la~iaic phase) and fro111 day 863 to day 1 13 (static phase). T o determine the feeding pattern, food consulanption was recorded twice daily (8.00 a.m. and 8.00 p.m.) for 1 week in each phase of hyperphagia. Body weight was nmeasuretf three times weeklj~. The average daily foocl consur~lption of hypothalanlic- hyperphagic rats was sig~mificantly higher than that of controls in both phases of hj.perphagir3 (27 1.50 versus 18 & 0.50 g/rat per da4- and 2ti & 1.50 versus 17 + 0.99 g/rat per day respectively, with P < 0.001 in each case). Figure 1 illustrates the food intake of hypothal;a~nic-hyperphagic rats. &&7hi8e riornlral control rats ate 28 & 1.95!&, the hyperpllagic rats ate 46 3.4$& of their daily rneal ira daytime duri~ag the dynamic phase. In the static phase, thtx hyperphagic: rats c.onsurmed 35 & 20.1% and the controls corasumed 27 =k 8.3% of their clxily meal in daytime. As shown in Fig. 2, significantly greater weiglat $rain ( P < 0.001) was observed in the dynamic phase but, i11 tlme static phase, rate of body lveight gain was not significantly diflureizt fro111 that oi the controls,
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M.\Y AXLP RE.4TON: IIUPEMPIIAGPA I N RAT 643
DYNAMIC PHASE
CONTROLS
STATIC PHASE
HYPOTHALAMIC - HY PERMAGIC
P
TIME - BAYS
FIG. I. Food intake of hypothalannic-hyperphagic. and contra[ rats. 'There was ;L reductiora of food intake in the controls following the test of I 3 l l uptale, whereas hyperphagic rats, being in the active hyperpliapic phase, did rrot shtaiv na~ich reductii~n in their intake. The effect of the test and (orj ether ane5thesia was niore obvious in the static phase9 i.e. days 96--99. Biesults art. exprecsed as rrlearr f S.E.M.
I I I I I I
0 18 20 38 40 5 0 68 80 90 100 110 TIME- DAYS
Fnc;. 2. Body weight gain of hypothalamic-hypcr1>hagic rats plotted against the tirne after operation. Nine rats were used in each group. Ether anesthesia used in ~neaselrcment of uptake cau3ed a temporary reduction in food intake and a corresponding reduction ira body weight gain in the control group in the dyncnmic phase a ~ i d in both groups irr the static phase. Results expressed as Insan f S.E.M.
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644 CANADIAN JOB'RNAL OF PHYSIOLOGY A N D I>IIA4RMACOLOGY. VOL. 44, 1966
although final body weight was much greater. Apparent decreased weight gains during studies of '"'I[ uptake were probably a consequence of the ether anes- thesia used to subdue the animals and not of the '"1 per se.
Spontaneous Running A cfiaity ?'en days after hypothalannic ablation, spontaneous activity of six control
and of six hypothrtlarnic-hyperphagic rats was ~laeasured for 7 days in activity cages. T o obtain the pattern of activity as well, activity was recorded twice daily (8.00 a.m. and 8.00 p.111.). ,After 7 days, the rats were retaarned to stcandard living cages. The ineasurenlent of spontaneous activity \\-as repeated in the static phase betlveen days 112 and 116. The circadian activity of hyperphagic rats recorded during both phases of hyperphagia renlained unchanged from that of intact controls. There appeared to 19e no relation between the feeding and activity patterns damring the dynainic phase, i.e. activity took place mainly i~x the dark hours whereas feeding was evenly distributed tli~rokaghout 24 hours (Table I). Spc~ntaneous ruixning activity (rev/rat per day) in hypo- thalamic-hyperphagic rats in the dynrtnlic phase was observed to be higher than that of co~ltrols.
'B'kII31,E I Spontaneous activity of hypothalamic-h) perphagic rats
- - -- - - - .- -- -- --- -- -- - - -- - .-
74 Activity No. of -4ctivit y, - - - - - - - - - - - --
Groiap rats rev/rat per day 8 a.m. - 8 p.m. 8 p.m. - 8 <l.tn.
Ilynamic phase: (clays 10-16) Coiitrols 6 B232f 83* 1 6 f 4 .8 84f 4.8 H ypothr~lramir-
h y perphagic 6 1'765f 170 IOf 2 .1 81f 2 . I P < 0.05
Static phase (days I1 2- 116) Cyontrols ) 1013f 150 29 f 3 . 1 71 f 3.1 Ilypothalarnic-
hyperlih,~gic- I 8l2f 194 37% 4 . 6 63% 4.6
Resting Oxygen Conszimption Westi~ig oxygen consuinption was measured according to the metlmod de-
scribed by Ferguso~n and Sellers (13). 011 the anorning of the experilllent (day 21) food was renzoved and 4 hours later, oxygen consunaption was determined in five kypotha1:amic-hyperphasic rats with an average body weight of 299 & 10.8 and in seven control rats weighing 282 =t 9.0 g. This test was repeated on day 95 when the hyperphagic rats weighed 495 & 15.4 g l ra t and the controls weighed 440 & 7.6 g/rat. I t is unfortunate that, in this experi~neixt, hyper- phagia was only moderate arid consequer-tt body weight i~ncreases were relatively small. No significant differences were observed in resting oxygen cornsumption, the vrillues (n~illiliters O2 consumed per kilogram per 2 minute) being for control and hypothalamic animals respectively: 14.7 & 0.83 and 12.8 & 1.13 (dynamic phase) ; 15.4 0.50 and 14.5 =t 0.18 (static ph;~se).
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MAY AND BEATON: HYPERPI-IAGIA I N RAT
I3lI Uptake by tlzc Thyroid 'Thyroidal uptalte of radioactive iodine ('"'I) was deternlined after provision
of an iodine-free diet for 2 weeks. 011 the day of the test, each rat in the hyperphagic and control groups received an intraperitoncal i~ljectioil of 0.5 pcurie %"I in I ml distilled water. Radioactivity over the thyroid was aneasured 24, 48. and 7 2 hours later, under light ether aiaesthcsla (to subdue the aninnals) with rt. scintillation probe counter. ITptake was calculated in counmts per ini~nutc after corrections were made for radioactive decay and background factors. This test was performed in both phases of hyperphagia (days 1-2-17 and days 96-99). Results of '"1 uptake and release are shown in Figs. 3 and 4 for the
CONTROLS (9 ) e..-.-e HYPOTHALAMIC-MYPERPHAGIC (9)
I500
TIME-DAYS TIME - DAYS
Flc,. 3- liptake and release of 13'1 by the thyroid of hypothal;r~lzic-h~lperphagic rats dtaring the dynamic phase c ~ f hyperphagia. Results expressed as mean f S.E.RII.
FIG. 4. IJptake and release of lU1I by the thyroid of hypothalamic-hy~>er~jhagic rats during the static phase of hyperpkagia. Iiesult~ expressed rts mean f S.E.M.
dynamic and static phases of hyperphagia respectively. Thyroidal uptake of "'1 by the llypothalanlic-layperphagric rats in the dyrmamic phase uras not different from that of controls (39 A 2.90 versus 36 A 2.6176 respectively). However, in the static phase, 1311 uptake was significa~ltly lower than control values (22.6 & 1.44 versus 9.5 & 1.64%), 1' < 0.02) and the subscqererlt rate of release of '"1 was si~nil:trly reduced.
S P I P ~ ~ ~ ~ - ~ ~ S Incorporation into Costal Cartilage T o exa~niile the possibility of changes in growth accompanying excessive body
weight gain in the dyna~nic phase of hyperphagia in our 11ypothaIamic rats, sulfate-% incorporation into costal cartilage was determined in the nlanner described by Collins and Baker (14), in six control and six hypothalarnic- hyperphagic rats (dynanlis phase). Ten ~nicrocuries of s5-s~llfat-e was injected intraperitoneally into each rat, which was killed 29 hours later. The seventh
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646 CANAl3IAN JOIJIPNAL OF PFIYSIO1,OGI' AND PHARMACOLOGY. VOL. 44, 1966
rib was removed and the incorporated radiosulfate was converted to Ba3504 and mounted on an aluminium planchet, radioactivity then being couilted with a gas-flow detector. Self-absorption was calculated to an infinite thinness and the results were calculated as counts per nniwute per milligranl wet weight of the tissue. T h e incorporation of Sinto costal cartilage was found to be rmorr-nal in the dynamic phase of hypothalamic hyperphagia, indicating no apparent effect of thc lesions upon skeletal growth. The values obtained were 5.8 A= 1.67 and 6.5 A= 1.50 c.p.nl. jnng tissue per minute for control and hyperphagic- rats respee tivel y . ,4~ethm;te-i-~~C C~ncorporation into L ip ids and the Release of Free Fatty Acids by
Adifiose Tissase in L7itro Incorporation of acet;tte-l-'*(gl into adipose tissue in vitro evas determined
according to the procedure of Baruch and Chailtoff (15) as modified by Ilolli- field and Parson (91, in eight hyperphagic and seven control rats (body weights 3'98 =t 20.1 g ancl 332 =t 13.6 g respectively) 27 days ;after production taf the hgipotl~alanlic lesions. 'H'hc test was repeated 131 days after the operatio11 (static phase) using seven hyperphagic rats (average body weight of 644 A= PS.1 g), One epididym~al lat pad from each of the same rats used in the nleasureriaent of acetate-I-"%' ialcorporation was used to measure the release of free fatty acids in vitrca ibccording to the procedure of Weaton et c ~ l . (16). In the present experirrnent , i ncorporatio~~ of acetate- 1-I4C: by adipose tissue of hypothzt lamic- hyperphagic rats in the dynai~nic phase was higher than that of controls, although statistical significance wes not obtained (Table 11). In the static
Acetate-l -14C ii~~c.orporatior~ and free fatty acid ( F F t I ) release by adipose tisqne of hypotha lainic-hyperphagic rats
- - -. - - -- - - - - - -- - - -- - - -- - - - -- - - - - - - - - - -- -- - - -- - - - - - - - - -- - - - -- - -- .
Dynamic phase Static phase - -
pmoIes FFA finnoles F'FA "C lipids, re!ease/iOO rng llC lipids, release/B00 mg
Gi -o~y c.p.m./g tissue tissue per 3 hr c.p.m./g tissue tissue per 3 kr - .- - -- -
Controls (7) 4061 f lOt).l* 0.67 A0.159 2495f 175 1.29f 0.13 ~ypotha'larkic-
hyperphagic ( 8 ) 9606 f 3660 0.21 k0.066 3664 ~ 4 0 8 0.57%0.11 P < 0.02 P < n. oa P < 0.02
NOTE: Acetate-l-16C added in each incubation medium was 2 ylnoles with an activity of 2 pcuriea. 'The nunlber of rats per group is in parentkaeses.
*,Mean f S.E.M.
phase, ho-tvever, a significantly higher lipsgenesis was ok~served in the rndiposc tissue of h?;p~t~lala~-~sic-kyper~IlIag~~ rats. In addia ion to this apparent increase in fat synthesis, lipolysis and release of free fatty acids were reduced in both phases of hyperphagia (Table 11).
14C-Glucose Incarpomtion ilato L ip ids nnd i ts Oxidation to C 0 2 i ~ z Adipose Il'z'ssue. oj' fIypothaL(~m kc-Hyperph~~g.ic Ka f s 1 7 2 Vitro
This test was carried out in the same manner as was the investigation of acetate- 1-C1* incorpora tion but glucose-L'-14C was used. (lollection and deter-
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MAY AND BEATOX: HYI'ERPHAGIA IN HAT 647
nlination of COz were done according to the procedure of Chernick, Masoro, and Ckaikoff (17). This experiment was done with six hyperphagic and six corltrol rats, 30 days after production of hypotklalarllic lesions. Tl-ne rats weighed 506 A 20.8 and 399 =I= 17.2 g respectively. The experiment was repeated on four hypothalamic rats which had received lesions 123 days previoaasly and o~-n six control rats. Incorporation of g l ~ c o s e - U - ~ T in to lipids appeared to be increased in both phases of hyperphagia, although statistical significance was not obtained (Table 111). Oxidation of glucose to COz was unchanged in either phase of hyperphagia.
Discussion Results of the present expcri~nents demonstrate, as has the work of others
(1, 2, 4), that two phases of hyperphagia, an early dynrttnic and a late static phase, can be distinguished in rats followiilg production of bilateral electrolytic lesions in the ventromedial region of the Imypothalaimus. Our l~arious experi- ~ne~ilts indicate also that care rnust be taken to identify the phase of hyperphagia when interpreting results, i.e. observations made during one phase are riot rlecessarily applicrtble to the other phase. 111 disc-ussing the present ot~servations it should be noted that nlale rats were used throughout; most of the observa- tions reported in the literature were made 011 female rats.
In the djynamic phase of hyperphagia, rats exhibited a sig~iificarnt increase in food intake and body weight gain act-ompanied by a change in the circactianl feeding pattern toward :an even distribution of feeding throughout the 24-hour period. Brooks (4) has previousljy noted this shift in feeding pattern during the dynamic phase. In the static phase of hyperphagia, although food intake remained a%~ove that of intact control ani~nsals and comparable to hypo- thalanlie rats in the dyrlanlic phrzse, body ~veight tended to~vinrd ;i plateau, although a t a considerably higher level than o1)servcd In controls. '%'his plateau 111aj- be explicable on the basis that, in the static phase, food intake per 100 g body weight was not greater than that of control animals and xvas less than that of hypothalanlic rats in the d j~~ lamic phase.
Our cxperime~its on the energy expendit alre of the hyp~tllal~t~nic-hyperphagic rats provided interesting results but their interpretation is difficult. Resting oxygen consunlpticrn tvas not significantly different fro111 that of cc~ntrc~ls in either plaase of hyperphagia, in accordance with the earlier observations of AIc~ntemurro and Stevenson (18) ; i t should be noted, however, that in our experiment on resting oxygen consumption, hyperphagia and i~ncrcascd weight gain were not as pro~lounced as our other experiments. I 'ptake and release bj- the thyroid of l3I in hypot11:zl:~illic-hyp@rphagi(- rats \lTas significaratly reduced in the static, but not in the dynanlic, p1m:tse. I t lalight be argued that the apparent decrease of lalI uptake is a consequence of injecting a fixed dose of I 3 l I into a larger anilnal, i.e. a dilution artifact. Monte~nmurro and Stevenson (IS) Bmave shown that the increased body weight of rats in the static phase is due allnost wholly to increased body fat, there being very little alteraticrn in the volume of extracellular fluid. A careful selarch of the literature did not
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648 CANADIAN JOC;KNXI, OF PHTSIOPJOGY ANL) PMARM,ZCOLOGY. VOP,. 44. 1968
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MAY ANT) RIISATON: HYPEKPHL4GIA I N RAT 641)
reveal any evidence that 13'1 can be trapped in or diluted by fat, nor is any adjustment made for body fat content when '?'I is used c'linically. I t would appear, therefore, that sorne degree of thyroid hypofurlction rriay exist in the hypothalamic-hyperphagic rat during the static phase, even though this was not apparent in the short-tern1 ~neasurement of resiing oxygen consumption. However, caution must be exercised in i~lterpretatiorl since another potential artifact is the possibility of differences in counting geometry due to effects of fat depots in the necks of hypothalamic aniilx~ls ; this might yield lower counting values. In the dynarnic phase a significant increase in spontaneous running activity was observed. I t is evident, however, that this increased energy expenditure was insufficient to balance the increased energy intake brought about by the hyperphagia, with the result that excessive weight gain occurred. Tha t this excessive weight gain did not indicate true growth is suggested 11y the finding of a normal i~lcorporation of 35S in costal cartilage. This is in agreement with the conclusion of EIctheri~lgton and Ranson (19) that hypo- thalamic-hyperphagic rats do not exhibit increased growth but nlay even have a decreased growth.
Our observations of itlcreascd Iipogenesis it1 vitro from 1-'4C-acetate and U-'4G-glucose 1~37 adipose tissue of hypothalamic-hyperphagic rats are of con- siderable interest. When considered along with the observed decrease in the release of free fatty acids by adipose tissue in vitro, these findings are consonant with a concept of increased synthesis and deposition, and decreased lipolysis of fat. Mankin et a%. (20), using deuteriurr-labelled fat in the diet, have sug- gested that in the hypothalamic-hyperphagic rat (static phase), there is no excessive absorption and deposition of fa t taut there is evidence of decreased mobilization. Whether our observations are related to the hyperphagia per sc or to the meal-eating pattern of these anitllals or to both is not clear. lileal eating is knoevil to increase Iipogenesis by adipose tissue in vitro (9, 10).
In summary, it would appear that in male rats, increased body weight gain during the dynamic phase of hypothalamic llyperphagia is a direct effect oh increased energy intake that is not balr~nced by increased apparent spoiataneous activity. Increased lipogenesis and decreased lipolg~sis are evident-; there is no evidei-ice of altered thyroid function. In the static phase, spontaneous activity is not increased, rlletabolic patterns are significantljy altered in the direciio~a of increased lipogerresis and decreased lipolysis, and there is suggestive evidence of thyroid hypofunction.
Acknowledgment The authors are grateful to Professor James ,4. F. Stevenson for his interest
and valuable criticisms throug-hout this investigatiot~.
References I. A. W. ~IETMEKINGTON and S, W. RANSON. I'roc. Soc. Exptl. Riol. itled. 41, 46.5 (1939). 2. A. I!'. ~IETHERINCTON and S. W. RANSON. Anat. Kec. 78, 149 (1'340). 3. J. TEPPERMAN, J . K. I ~ H O R E C K , and C . N. 11. EON<;. !\ma J. I'hysiol. 133, 468 (1941).
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650 CANADIAN JOURNAL OF PHYSIOLOGY A N D PIIAR&I.IA@OLOGU. VOL. 44, 1966
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