METABOLIC EFFECTS OF HYPERPHAGIA IN THE HYPOTHALAMIC-HYPERPHAGIC RAT

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<ul><li><p>hlETABOLIC EFFECTS OF HYPERPIIAGIA IK THE HYPOTHA4LAMIC-HYPERPHA4GIC RAT1*" </p><p>K. I.;. J l,ah- of hyperphagia have been investigated i l l inale rats in which </p><p>h3perphagia ~3~ induced by bilateral, electrolytic Iehions in the regisla of the ventromedi;iI nuclei of the hp pothalamu&gt;. 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, &amp;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. </p><p>Introduction tIyperphagi;i is known to occur after bilateral electrolytic lesions are 111acle </p><p>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 &amp;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). </p><p>In view of these observatioals, the present experi~nents were perfornled to </p><p>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 </p><p>of *\Vestern Oaltrarin, in partial fulfill~nent of the requirements for the llegree of Master of Scaence. </p><p>T~olornbo I;ellow. Present addresb: 1)epartment of 13hysioL,gy, Medical School, hlandalay, H~iriraa. </p><p>Ahfed ical Research Alswciate of the Wledical Icesearch Council of C;lnada. </p><p>('anaclian J:brlr~~al of P1lysi:)logy and I'har~nacology. Volume I4 (19ii(;) </p><p>Can</p><p>. J. P</p><p>hysi</p><p>ol. P</p><p>harm</p><p>acol</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.n</p><p>rcre</p><p>sear</p><p>chpr</p><p>ess.</p><p>com</p><p> by </p><p>YO</p><p>RK</p><p> UN</p><p>IV o</p><p>n 11</p><p>/21/</p><p>14Fo</p><p>r pe</p><p>rson</p><p>al u</p><p>se o</p><p>nly.</p></li><li><p>64'2 CANADIAN JOURNAL OF PPIYSIBLOGY AND f'I1XRMA.VO~Gk'. VOL. 44, 19fiii </p><p>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. </p><p>Experimental and Results ?adult rlinle rats of the 6Vistar strain, with an iiaitiaI body weight of about </p><p>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 &amp; 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. </p><p>Food Putnke, Pieeding Pattern, (end Body Weight Chin 'Fhe average daily food intake of imiile hy~~othala~nic-hyperphagic anti tlne </p><p>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 &amp; 0.50 g/rat per da4- and 2ti &amp; 1.50 versus 17 + 0.99 g/rat per day respectively, with P &lt; 0.001 in each case). Figure 1 illustrates the food intake of hypothal;a~nic-hyperphagic rats. &amp;&amp;7hi8e riornlral control rats ate 28 &amp; 1.95!&amp;, the hyperpllagic rats ate 46 3.4$&amp; of their daily rneal ira daytime duri~ag the dynamic phase. In the static phase, thtx hyperphagic: rats c.onsurmed 35 &amp; 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 &lt; 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, </p><p>Can</p><p>. J. P</p><p>hysi</p><p>ol. P</p><p>harm</p><p>acol</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.n</p><p>rcre</p><p>sear</p><p>chpr</p><p>ess.</p><p>com</p><p> by </p><p>YO</p><p>RK</p><p> UN</p><p>IV o</p><p>n 11</p><p>/21/</p><p>14Fo</p><p>r pe</p><p>rson</p><p>al u</p><p>se o</p><p>nly.</p></li><li><p>M.\Y AXLP RE.4TON: IIUPEMPIIAGPA I N RAT 643 </p><p>DYNAMIC PHASE </p><p>CONTROLS </p><p>STATIC PHASE </p><p>HYPOTHALAMIC - HY PERMAGIC </p><p>P </p><p>TIME - BAYS FIG. I. Food intake of hypothalannic-hyperphagic. and contra[ rats. 'There was ;L reductiora </p><p>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. </p><p>I I I I I I </p><p>0 18 20 38 40 5 0 68 80 90 100 110 TIME- DAYS </p><p>Fnc;. 2. Body weight gain of hypothalamic-hypcr1&gt;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. </p><p>Can</p><p>. J. P</p><p>hysi</p><p>ol. P</p><p>harm</p><p>acol</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.n</p><p>rcre</p><p>sear</p><p>chpr</p><p>ess.</p><p>com</p><p> by </p><p>YO</p><p>RK</p><p> UN</p><p>IV o</p><p>n 11</p><p>/21/</p><p>14Fo</p><p>r pe</p><p>rson</p><p>al u</p><p>se o</p><p>nly.</p></li><li><p>644 CANADIAN JOB'RNAL OF PHYSIOLOGY A N D I&gt;IIA4RMACOLOGY. VOL. 44, 1966 </p><p>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. </p><p>Spontaneous Running A cfiaity ?'en days after hypothalannic ablation, spontaneous activity of six control </p><p>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. </p><p>'B'kII31,E I Spontaneous activity of hypothalamic-h) perphagic rats </p><p>- - -- - - - .- -- -- --- -- -- - - -- - .- </p><p>74 Activity No. of -4ctivit y, - - - - - - - - - - - -- </p><p>Groiap rats rev/rat per day 8 a.m. - 8 p.m. 8 p.m. - 8 </p></li><li><p>MAY AND BEATON: HYPERPI-IAGIA I N RAT </p><p>I3lI Uptake by tlzc Thyroid 'Thyroidal uptalte of radioactive iodine ('"'I) was deternlined after provision </p><p>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 </p><p>CONTROLS (9 ) e..-.-e HYPOTHALAMIC-MYPERPHAGIC (9) </p><p>I500 </p><p>TIME-DAYS TIME - DAYS Flc,. 3- liptake and release of 13'1 by the thyroid of hypothal;r~lzic-h~lperphagic rats dtaring </p><p>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~&gt;er~jhagic rats during </p><p>the static phase of hyperpkagia. Iiesult~ expressed rts mean f S.E.M. </p><p>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 &amp; 1.44 versus 9.5 &amp; 1.64%), 1' &lt; 0.02) and the subscqererlt rate of release of '"1 was si~nil:trly reduced. </p><p>S P I P ~ ~ ~ ~ - ~ ~ S Incorporation into Costal Cartilage T o exa~niile the possibility of changes in growth accompanying excessive body </p><p>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 </p><p>Can</p><p>. J. P</p><p>hysi</p><p>ol. P</p><p>harm</p><p>acol</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.n</p><p>rcre</p><p>sear</p><p>chpr</p><p>ess.</p><p>com</p><p> by </p><p>YO</p><p>RK</p><p> UN</p><p>IV o</p><p>n 11</p><p>/21/</p><p>14Fo</p><p>r pe</p><p>rson</p><p>al u</p><p>se o</p><p>nly.</p></li><li><p>646 CANAl3IAN JOIJIPNAL OF PFIYSIO1,OGI' AND PHARMACOLOGY. VOL. 44, 1966 </p><p>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 </p><p>Adifiose Tissase in L7itro Incorporation of acet;tte-l-'*(gl into adipose tissue in vitro evas determined </p><p>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 </p><p>Acetate-l -14C ii~~c.orporatior~ and free fatty acid ( F F t I ) release by adipose tisqne of hypotha lainic-hyperphagic rats </p><p>- - -. - - -- - - - - - -- - - -- - - -- - - - -- - - - - - - - - - -- -- - - -- - - - - - - - - -- - - - -- - -- . Dynamic phase Static phase </p><p>- - pmoIes FFA finnoles F'FA </p><p>"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 </p><p>- .- - -- - </p><p>Controls (7) 4061 f lOt).l* 0.67 A0.159 2495f 175 1.29f 0.13 ~ypotha'larkic- </p><p>hyperphagic ( 8 ) 9606 f 3660 0.21 k0.066 3664 ~ 4 0 8 0.57%0.11 P &lt; 0.02 P &lt; n. oa P &lt; 0.02 </p><p>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. </p><p>*,Mean f S.E.M. </p><p>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). </p><p>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 </p><p>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- </p><p>Can</p><p>. J. P</p><p>hysi</p><p>ol. P</p><p>harm</p><p>a...</p></li></ul>

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