Physiological Effects of Food Carbohydrates - ACS Publications

3 Factors Influencing Adipose Tissue Response to Food Carbohydrates 1

Downloaded by EAST CAROLINA UNIV on June 4, 2018 | https://pubs.acs.org Publication Date: June 1, 1975 | doi: 10.1021/bk-1975-0015.ch003

DALE R. ROMSOS and GILBERT A. L E V E I L L E Food Science and Human Nutrition, Michigan State University, East Lansing, Mich. 48824

Interest has been renewed on the influence of dietary car bohydrates in human nutrition. Not only is the quantity of carbohydrate in the diet changing but the types of carbohydrate consumed by the Western World has also changed during the past 50 years. These changes, in some cases, have been implicated as a contributing factor to numerous diseases. For example, sucrose has been implicated as a major factor in the development of cardiovascular disease (1). However, it should be pointed out that not all researchers are in agreement on this point (2, 3). In this review we will discuss our efforts to understand the role of dietary carbohydrate in the control of adipose tis sue fatty acid synthesis. Since the metabolic response of one organ, in some cases, influences metabolism in another organ, our studies have involved lipid metabolism in liver as well as in adipose tissue. Dietary Factors Influencing Adipose Tissue Response to Carbo hydrates Studies concerning the influence of the quantity of car bohydrate in the diet on adipose tissue fatty acid synthesis are complex since modification of one dietary variable imposes a change on another d i e t a r y v a r i a b l e . F r e q u e n t l y d i e t a r y c a r bohydrate and f a t are interchanged i n s t u d i e s on the i n f l u e n c e of d i e t on l i p i d metabolism. I f the carbohydrate content of the d i e t i s m o d i f i e d without a concomitant change i n another n u t r i e n t , the n u t r i e n t :energy r a t i o of the d i e t i s changed. G e n e r a l l y a r e d u c t i o n i n the carbohydrate content of the d i e t w i l l depress f a t t y a c i d s y n t h e s i s i n adipose t i s s u e prepar a t i o n s of both r a t s and p i g s ; however, there are e x c e p t i o n s .

Supported by Grant HL-14677 from the N a t i o n a l I n s t i t u t e of H e a l t h , U.S. P u b l i c H e a l t h S e r v i c e . J o u r n a l A r t i c l e No. 7023 Michigan A g r i c u l t u r e Experiment S t a t i o n . 46 Jeanes and Hodge; Physiological Effects of Food Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

Library EmerTcsn Chemical Society


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47

These exceptions may a i d i n our understanding of the c o n t r o l o f l i p i d metabolism i n adipose t i s s u e . S u b s t i t u t i o n of mediumc h a i n - t r i g l y c e r i d e s (MCT) f o r d i e t a r y glucose d i d not i n f l u e n c e adipose t i s s u e l i p o g e n e s i s i n the r a t even though the carbohydrate content of the d i e t was decreased (4) (Table 1). L i p o genesis i n p i g adipose t i s s u e was depressed l e s s by the a d d i t i o n of 10% MCT to the d i e t than by the a d d i t i o n of l a r d o r corn o i l (5) (Table 1). S i m i l a r l y , replacement o f d i e t a r y g l u cose with 1,3-butanediol (BD) d i d not depress adipose t i s s u e l i p o g e n e s i s i n the r a t o r p i g (6, 7) (Table 2). Thus, i t i s apparent that the r o l e o f carbohydrate content of the d i e t i n the r e g u l a t i o n of adipose t i s s u e metabolism i s complex and i n v o l v e s i t s r e l a t i o n s h i p with other d i e t a r y i n g r e d i e n t s . Both MCT and BD have marked i n f l u e n c e s on h e p a t i c metabolism (4,6, 8). T h e i r metabolism e l e v a t e s c i r c u l a t i n g ketone body l e v e l s . P r e f e r e n t i a l o x i d a t i o n of ketone bodies by muscle would spare glucose f o r use i n adipose t i s s u e . TABLE 1. IN VITRO FATTY ACID SYNTHESIS IN ADIPOSE TISSUE FROM RATS AND PIGS FED MEDIUM-CHAIN TRIGLYCERIDES Diet Species

Control

MCT

Rat

1143 + 63

1170 + 72

Pig

659 + 46

526 + 28

From (4) and (5). D i e t s fed f o r 3 weeks. Rat - 12% MCT. P i g - 10% IjjIgT. F a t t y a c i d s y n t h e s i s expressed as nmoles glucose-U- C i n c o r p o r a t e d i n t o f a t t y acids/100 mg t i s s u e / 2 hr. TABLE 2.

IN VITRO FATTY ACID SYNTHESIS IN ADIPOSE TISSUE FROM RATS AND PIGS FED BUTANEDIOL Diet 17% BD energy

Species

Control

Rat

844 + 77

700

Pig

184 + 28

250 + 29

7 2

±

From (6) and (7). D i e t s ^ f e d f o r 3 weeks. R e s u l t s expressed as nanomoles glucose-U- C i n c o r p o r a t e d i n t o f a t t y acids/100 mg t i s s u e / 2 hr.

Jeanes and Hodge; Physiological Effects of Food Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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• 4 0 0 \- Fructose Fed Substrate Glucose-U- C I4

300r-

Fructose-U- C ,4

2 00 Ο

l o o

50

100

150

200

Substrate concentration, m M

Biochimica et Biophysica Acta

Figure 1.

14

14

In vitro conversion of glucose-U- C and fructose-U- C to fatty acids in liver slices from glucose- or fructose-fed rats (19)


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LEVEiLLE

P a t t e r n of food intake a l s o a l t e r s adipose t i s s u e l i p i d metabolism. The c a p a c i t y of adipose t i s s u e preparations from meal-fed r a t s o r pigs to convert carbohydrate t o f a t t y a c i d s i s increased d r a m a t i c a l l y (9,10). Thus, i t i s apparent that f a c t o r s which a l t e r the p a t t e r n of carbohydrate intake may a l s o i n f l u e n c e l i p i d metabolism i n adipose t i s s u e . The remainder of our d i s c u s s i o n w i l l center on the i n f l u e n c e of d i e t a r y f r u c t o s e on adipose t i s s u e metabolism.


I n t e s t i n a l Transport

and P e r i p h e r a l

Fructose

Levels

V i r t u a l l y a l l species studied can absorb and u t i l i z e f r u c tose. However, i t i s important to recognize that the i n t e s t i n e has s p e c i e s - s p e c i f i c i n f l u e n c e s on f r u c t o s e metabolism. In the guinea p i g and hamster f r u c t o s e i s l a r g e l y converted to glucose during t r a n s f e r across the i n t e s t i n a l w a l l whereas i n other s p e c i e s , i n c l u d i n g man, the l a b o r a t o r y rat, and the c h i c k * f r u c tose i s absorbed l a r g e l y unchangçjï (11). The chick absorbed approximately 85% of a f r u c t o s e - C dose unchanged (11). In the r a t at l e a s t , f r u c t o s e absorption appears to occur v i a an a c t i v e carrier-mediated mechanism (12,13). Thus, i t i s apparent that i n a c o n s i d e r a t i o n of the i n f l u e n c e of d i e t a r y f r u c t o s e on adipose t i s s u e metabolism one must be aware of the s p e c i e s s p e c i f i c response of the i n t e s t i n e to f r u c t o s e . Feeding d i e t s c o n t a i n i n g f r u c t o s e to species that absorb f r u c t o s e i n t a c t increases the p o r t a l v e i n concentration of f r u c tose markedly; however, p e r i p h e r a l c i r c u l a t i n g l e v e l s of f r u c tose are elevated to a much l e s s e r extent (14). This has been taken to i n d i c a t e that hepatic metabolism of f r u c t o s e i s extensive. D i e t a r y Fructose

and Hepatic and Adipose Tissue

Lipogenesis

I t i s c l e a r that s u b s t i t u t i n g f r u c t o s e f o r glucose i n the d i e t of r a t s leads to changes i n l i p i d metabolism. To increase our understanding of the i n f l u e n c e of d i e t a r y carbohydrates on metabolism we have examined h e p a t i c and adipose t i s s u e responses to d i e t a r y f r u c t o s e . I t i s g e n e r a l l y accepted that feeding f r u c t o s e to r a t s increases the r a t e of f a t t y a c i d synthesis i n the l i v e r ; however, r e s u l t s from i n v i t r o estimates of hepatic f a t t y a c i d synthesis are not a l l i n agreement (15,16,17,18). We examined the i n f l u e n c e of s u b s t r a t e source and concent r a t i o n on h e p a t i c l i p o g e n e s i s i n r a t s ^ f e d glucose or f r u c t o s e c o n t a i n i n g d i e t (Figure 1). Glucose- C conversion to f a t t y a c i d s increased as the concentration of substrate increased, probably r e l a t e d to the a b i l i t y of high l e v e l s of glucose to saturate ç^ucokinase and thus increase a c e t y l CoA formation. Fructose-^ C conversion to hepatic f a t t y acids was higher than glucoseC conversion to f a t t y acids when the substrate con-



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c e n t r a t i o n was 10 mM; however as s u b s t r a t e concentration was i n c r e a s e d , h e p a t i c conversion of f r u c t o s e to f a t t y a c i d s was markedly decreased. T h i s decrease i n f r u c t o s e conversion to f a t t y acids when the f r u c t o s e l e v e l i n the i n c u b a t i o n media exceeded 50 mM was probably r e l a t e d to the r a p i d phosphorylation of f r u c t o s e and the subsequent decrease i n ATP l e v e l s . We measured ATP l e v e l s i n l i v e r s l i c e s and observed that ATP l e v e l s were depressed by more than 50% when the media contained 100 mM f r u c t o s e r a t h e r than 100 mM glucose (19). We then examined i n v i v o adenine n u c l e o t i d e l e v e l s i n l i v e r from r a t s fed glucose or f r u c t o s e . ATP l e v e l s were elevated i n l i v e r s of r a t s fed f r u c t o s e (Table 3). Whether t h i s i n c r e a s e i n h e p a t i c ATP l e v e l would allow r a t s consuming a l a r g e dose of f r u c t o s e , such as might occur i n meal-fed animals, to more e f f e c t i v e l y dispose of t h i s dose under i n v i v o c o n d i t i o n s remains to be e s t a b l i s h e d . TABLE 3.

EFFECT OF DIETARY FRUCTOSE AND GLUCOSE ON LIVER ADENINE NUCLEOTIDE LEVELS IN VIVO D i e t a r y Carbohydrate Glucose

Fructose

ATP

25

39

ADP

9

11

AMP

6

5

ym/liver

From (19).

D i e t s were fed f o r 3 weeks.

Various techniques have been employed to o b t a i n i n v i v o estimates of f a t t y a c i d s y n t h e s i s i n r a t s fed v a r i o u s carbohydrates. O r a l , i n t r a p e r i t o n e a l or intravenous a d m i n i s t r a t i o n of a t r a c e r dose of l a b e l e d substrate i s complicated by p o s s i b l e d i f f e r e n c e s i n r a t e s of substrate absorption, by i n t e s t i n a l metabolism of the substrate or by p o s s i b l e i s o t o p e ^ d i l u t i o n e f f e c t s at the t i s s u e l e v e l . We e l e c t e d to u t i l i z e H-labeled water as a t o o l to obtain t o t a l r a t e s of f a t t y a c i d s y n t h e s i s , l a r g e l y independent of the source of a c e t y l groups which are incorporated i n t o f a t t y a c i d s . I t i s c l e a r that the i n v i v o r a t e of f a t t y a c i d synthesis i n l i v e r of f r u c t o s e fed r a t s was higher than observed i n glucose fed animals (Table 4).


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EFFECT OF DIETARY CARBOHYDRATE ON IN VIVO FATTY ACID SYNTHESIS D i e t a r y Carbohydrate Tissue Liver

47 + 6

80 + 13

E x t r a Hepatic

14 + 1

7+1

From (19). Downloaded by EAST CAROLINA UNIV on June 4, 2018 | https://pubs.acs.org Publication Date: June 1, 1975 | doi: 10.1021/bk-1975-0015.ch003

Fructose

Glucose

Results expressed as dpm χ 10

per gram.

Recognizing that d i e t a r y f r u c t o s e elevated the r a t e of h e p a t i c l i p o g e n e s i s , we examined l i p i d metabolism i n adipose t i s s u e , the predominant l i p o g e n i c organ i n the r a t , of r a t s f e d fructose. In çgididymal adipose t i s s u e , f a t t y a c i d s y n d e s i s from f r u c t o s e - C was lower than observed from glucoseC regardless of d i e t a r y carbohydrate f e d (Table 5 ) . Further, d i e t a r y f r u c t o s e depressed l i p o g e n e s i s from both s u b s t r a t e s . These r e s u l t s suggested to us that the r e l a t i v e importance of the adipose t i s s u e to f a t t y a c i d s y n t h e s i s may be decreased i n f r u c t o s e - f e d r a t s . Estimates of the i n v i v o r a t e of f a t t y a c i d synthesis obtained with t r i t i a t e d water a l s o i n d i c a t e d that the e x t r a h e p a t i c r a t e of f a t t y a c i d s y n t h e s i s was decreased i n r a t s fed f r u c t o s e (Table 4 ) . Although the t o t a l r a t e of f a t t y a c i d s y n t h e s i s i n r a t s f e d f r u c t o s e was unchanged, the r e l a t i v e importance of the l i v e r was increased and that of the e x t r a hep a t i c t i s s u e s decreased when f r u c t o s e , r a t h e r than glucose, was fed to r a t s . TABLE 5.

INFLUENCE OF DIETARY CARBOHYDRATE SOURCE ON IN VITRO FATTY ACID SYNTHESIS IN RAT ADIPOSE TISSUE D i e t a r y Carbohydrate

Substrate 14 C 14 Fructose-U- C Glucose-U-

Glucose

Fructose

540 + 61

271 + 57

191 + 19

87 + 26

From (19). Results expressed as nmoles substrate converted to f a t t y a c i d s per 100 mg t i s s u e per 2 h r s .



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Several f a c t o r s are probably i n v o l v e d i n t h i s s h i f t i n metabolism i n the presence of d i e t a r y f r u c t o s e . Froesch (20) has r e c e n t l y reviewed f r u c t o s e metabolism i n adipose t i s s u e . He noted that f r u c t o s e t r a n s p o r t i n t o the adipocyte appears to be mediated by a c a r r i e r w i t h a r e l a t i v e l y high apparent Κ f o r f r u c t o s e ; thus s i g n i f i c a n t t r a n s p o r t of f r u c t o s e occurs onTy when blood f r u c t o s e l e v e l s are h i g h . F u r t h e r , i n s u l i n does not s t i m u l a t e f r u c t o s e uptake by r a t adipose t i s s u e . Since adipose t i s s u e l a c k s f r u c t o k i n a s e , hexokinase i s probably i n v o l v e d i n the phosphorylation o f f r u c t o s e i n t h i s t i s s u e . P h y s i o l o g i c a l l y , f r u c t o s e - C conversion t o f a t t y a c i d s i n r a t adipose t i s s u e probably occurs^only a f t e r p r i o r h e p a t i c conversion of f r u c t o s e C t o glucose- C. One of the key c o n t r o l p o i n t s i n the conversion of d i e t a r y carbohydrate t o f a t t y a c i d s i n r a t adipose t i s s u e i s at the l e v e l of glucose entry i n t o the adipocyte, an i n s u l i n dependent process. Thus, v a r i o u s d i e t a r y carbohydrates might i n f l u e n c e f a t t y a c i d s y n t h e s i s i n adipose t i s s u e v i a t h e i r e f f e c t on c i r c u l a t i n g i n s u l i n l e v e l s . Bruckdorfer e t a l (21) have demon s t r a t e d that r a t s f e d f r u c t o s e have lower c i r c u l a t i n g i n s u l i n l e v e l s than do r a t s f e d glucose. A l s o , an o r a l dose of f r u c t o s e does not i n c r e a s e plasma i n s u l i n l e v e l s i n f a s t e d r a t s whereas a comparable glucose load doubled plasma i n s u l i n l e v e l s . Results of these s t u d i e s suggest that the r a p i d metabolism of f r u c t o s e by the l i v e r coupled w i t h lower c i r c u l a t i n g i n s u l i n l e v e l s i n f r u c t o s e f e d r a t s c o n t r i b u t e to the decreased r a t e of f a t t y a c i d s y n t h e s i s observed i n these r a t s . Conclusions

and Speculation

D i e t a r y carbohydrates do i n f l u e n c e adipose t i s s u e f a t t y a c i d s y n t h e s i s i n r a t s and p i g s . One of the key c o n t r o l p o i n t s i n the conversion of d i e t a r y carbohydrates t o f a t t y a c i d s i s a t the l e v e l of glucose entry i n t o the adipocyte, an i n s u l i n de pendent process. A r e d u c t i o n i n carbohydrate i n t a k e g e n e r a l l y would be expected t o depress i n s u l i n s e c r e t i o n ; however i f com pounds r e a d i l y converted t o ketones, such as MCT o r BD, are sub s t i t u t e d f o r the carbohydrate p o r t i o n of the d i e t i n s u l i n , s e c r e t i o n might not decrease s i n c e ketones a l s o s t i m u l a t e i n s u l i n r e l e a s e . Meal-eating a l s o increases i n s u l i n r e l e a s e and glucose s t i m u l a t e s a greater i n s u l i n r e l e a s e than does f r u c t o s e . I f the adipocyte maintains i t s s e n s i t i v i t y t o i n s u l i n , these d i e t a r y c o n d i t i o n s would be expected to increase glucose entry i n t o the c e l l thereby s t i m u l a t i n g f a t t y a c i d s y n t h e s i s . The r o l e of d i e t a r y f a c t o r s i n m a i n t a i n i n g i n s u l i n s e n s i t i v i t y of the a d i pocyte are not c l e a r .


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Literature Cited

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Yudkin, J. Proc. Nutr. Soc. (1972) 31, 331-337. Walker, A. R. P. Atherosclerosis (1971) 14, 137-152. Keys, A. Atherosclerosis (1971) 14, 193-202. Wiley, J. Η., and Leveille, G. A. J. Nutr. (1973) 103, 829-835. Allee, G. L., Romsos, D. R., Leveille, G. A. and Baker, D. H. Proc. Soc. Exp. Biol. Med. (1972) 139, 422-427. Romsos, D. R., Sasse, C. and Leveille, G. A. J. Nutr. (1974) 104, 202-209. Romsos, D. R., Belo, P. S., Miller, E. R. and Leveille, G. A. J. Nutr. (1974) Submitted. Romsos, D. R., Belo, P. S. and Leveille, G. A. J. Nutr. (1974) 104, In press. Leveille, G. A. J. Nutr. (1967) 91, 25-34. Allee, G. L., Romsos, D. R., Leveille, G. A. and Baker, D. H. J. Nutr. (1972) 102, 1115-1122. Leveille, G. Α., Akinbami, T. K. and Ikediobi, C. O. Proc. Soc. Exp. Biol. Med. (1970) 135, 483-486. Macrae, A. R. and Neudoerffer, T. S. Biochim. Biophys. Acta (1972) 288, 137-144. Gracey, M., Burke, V. and Oshin, A. Biochim. Biophys. Acta (1972) 266, 397-406. Topping, D. L. and Mayes, P. A. Nutr. Metabol. (1971) 13, 331-338. Chevalier, M. M., Wiley, J. H. and Leveille, G. A. J. Nutr. (1972) 102, 337-342. Zakim, D., Pardini, R. S., Herman, R. H. and Sauberlich, H. E. Biochim. Biophys. Acta (1967) 144, 242-251. Kritchevsky, D. and Tepper, S. A. Med. Exp. (1969) 19, 329-341. Bender, A. E. and Thadoni, P. V. Nutr. Metabol. (1970) 12, 22-39. Romsos, D. R., and Leveille, G. A. Biochim. Biophys. Acta (1974) 360, 1-11. Froesch, E. R. Acta Med. Scand. (1972) Suppl. 542, 37-46. Bruckdorfer, K. R., Khan, I. H., and Yudkin, J. Biochem. J. (1972) 129,439-445.


Physiological Effects of Food Carbohydrates - ACS Publications

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