Effect of a high-fat diet on obese-hyperglycaemic and non-obese Bar Harbor mice

Diabetologia, Oct 1971

Dietary obesity induced by a high-fat diet was superimposed in mice already suffering from the hereditary obese-hyperglycaemic (O-H) syndrome. Six-weekold animals given a diet containing 41.5% lard for 4.5 months gained 150% more weight than those given a control 78.3% wheat flour diet. There was only a slightly significant difference in weight gain of the lean littermates given the same two diets. — The interaction of the high-fat diet and the ob/ob genotype led to a further enlargement of adipose cells and an increased number of mast cells in epididymal fat. Diabetes was not aggravated in spite of a reduction in the levels of serum insulin, and in the insulin content of the pancreas. —The contribution of lipogenesis and dietary fat to the development of this obesity of mixed origin was estimated from an analysis of the fatty acid distribution in the diet, in three fat pads (epididymal, perirenal and subcutaneous), and in the liver. From the linoleate contents, it follows that fat depot in O-H mice on a high-fat diet was made up of 4 times more exogenous fatty acids than endogenous acids, but in spite of this, net lipogenesis was hardly affected. Therefore, obese-hyperglycaemic mice have a tremendous capacity to deposit and retain any kind of fat. The fatty acid spectrum also indicates that a large portion of the dietary supply of palmitate and stearate was converted into palmitoleate and oleate.

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Effect of a high-fat diet on obese-hyperglycaemic and non-obese Bar Harbor mice

Effect of a High-Fat Diet on 0bese-Hyperglycaemic and Non-0bese Bar Harbor Mice Diabetologia 0 0 Laboratoire de Biologie du C.N.A.M. et de N u t r i t i o n H u m a i n e de I'I.N.S.E.R.M., Paris, France, and D e p a r t m e n t of Biochemistry a n d Nutrition, Brussels University School of Medicine , Brussels , Belgium l~eceived: F e b r u a r y 23, i 9 7 i , accepted: J u l y 22, 197i Summary. D i e t a r y obesity induced b y a high-fat diet was superimposed in mice a l r e a d y suffering from the h e r e d i t a r y obese-hyperglyeaemic (O-H) syndrome. Sixweekold animals given a diet containing 41.5% lard for 4.5 months gained 150% more weight t h a n those given a control 78.3% wheat flour diet. There was only a slightly significant difference in weight gain of the lean littermates given the same two diets. -- The interaction of the high-fat diet and the ob/ob genotype led to a further enlargement of adipose cells and an increased number of mast cells in e p i d i d y m a l fat. Diabetes was not a g g r a v a t e d in spite of a reduction in the levels of serum insulin, a n d in the insulin content of the pancreas. -The contribution of lipogenesis a n d d i e t a r y fat to the development of this obesity of m i x e d origin was estimated from an analysis of the f a t t y acid distribution in the diet, in three fat pads (epididymal, perirenal and subcutaneous), and in the liver. F r o m the linoleate contents, it follows t h a t fat d e p o t in O-H mice on a high-fat diet was m a d e up of 4 times more exogenous f a t t y acids t h a n endogenous acids, b u t in spite of this, net lipogenesis was h a r d l y affected. Therefore, obese-hyperglycaemic mice have a tremendous capacity to deposit a n d retain a n y kind of fat. The f a t t y acid spectrum also indicates t h a t a large portion of the d i e t a r y supply of p a l m i t a t e and stearate was converted into palmitoleate a n d oleate. - Effets d'un rdgime riehe en lipides sur los souris ob~seshyperglycgmiques de Bar Harbor et leurs contrdles nonob~ses. J~dsumg. Une obdsitd nutritionnelle est imposde ~ des souris souffrant dgj~ du syndrome cong6nital obdsit6hyperglyc6mie (O-H). Des a n i m a u x de 6 semaines qui regoivent un r~gime contenant 41.5% de lard p e n d a n t 4.5 mois subissent un gain pond6ral dgpassant de 150% celui observ6 avec un rdgime ~ base de 78.3% de farine. Chez les souris non-ob~ses la diff6rcnce de poids provoqude p a r les deux r6gimes est ~ peine signifieative. -- L'interaction d u r6gime gras et du gdnotype ob/ob aceentue l'hypertrophie des adipocytes et augmente le nombre des mastocytes dens la graisse ~pididymaire. Le diab~te n ' e s t pas aggrav~ malgr4 une r6duction de l'insulindmie et du eontenu pancr4atique en insuline. -- L a contribution de la lipogen~se et du lard eonsomm6 au d6veloppement de cette ob6sit~ m i x t e peut 8ire appr6ci4e en a n a l y s a n t la distribution des acides gras dens le r6gime, dens trois pannieules adipeux (dpididymaire, pdrir6nal et souscutan6) et dens le foie. Le contenu cn linoldate indique que la graisse ddpos6e p a r la souris O-I-I au r~gime gras contient 4 fois plus d'acides gras exog~nes que d'acides gras endog~nes et que la lipogcn~se nette n'est gu~re r6duite. L a souris O-H a done une a p t i t u d e exceptionnelle d6poser et ~ retenir de la graisse, quelle que soft l'origine de cette derni~re. Une proportion i m p o r t a n t e du p a l m i t a t e et du st6arate ing6rds est eonvertie p a r ailleurs en palmitol~ate et ol6ate. Zusammenfassung. F e t t s u c h t , die durch fettreiche Kost induziert wird, t r a t bei genetisch fettsiichtigen und hyperglyk~imischen Miiusen (O-H) in verst~irktem Mal~e auf. Sechs Wochen alte Tiere erhielten eine Di~t m i t einem F e t t g e h a l t yon 41.5 %. Nach 4 ~ Monatcn lag des K6rpergewieht u m 150% h6her als bei der Kontrollgruppe, die eine Digit m i t einem K o h l e n h y d r a t a n t e i l yon 78.3% bek o m m e n hatte. ])as K6rpergewicht nicht fettsiichtiger Kontrolltiere zeigte nach Vorbehandlung mit beiden Di~iten nur geringgradige Unterschiede. ])as Zusammentreffen di~tetisch induzierter und genetisch determinierter F e t t sucht fiihrte zu weiterer Zellvergr61~erung und zunehmender Zahl der 1Viastzellen im epididymalen F e t t a n h a n g . Obgleieh die Seruminsulinspiegel und der Pankreasinsulingehalt abnahmen, t r a t keine Verscblechterung der diabetischen Stoffwechsellage auf. I)er Anteil yon Lipogenese und exogener F e t t z u f u h r an der Entwicklung dieser F e t t s u e h t s f o r m wurde durch Analysen der Fettsiiuren in dcr Dis des epididymalen, perirenalen und s u b k u t a n e n Fettgewebes und der Leber gesch~itzt. Aus dem Gehalt an Linols~ure l~tllt sich schlieBen, dart des F e t t d e p o t yon O-H M~usen naeh fettreicher I)i~it eine vierfach grbttere Menge exogener als endogener Fetts~inren enth~lt und die Nettolipogenese k a u m reduziert ist. Genetiseh fettsiichtige und hyperglyk~imisehe M~iuse haben demnach eine aul~erordentlich hohe K a p a z i t ~ t F e t t zu speichern. Das Fetts~iurespektrum zeigt weiterhin, dal~ ein groBer Anteil der m i t der N a h r u n g zugefiihrten 1)almitins~ure und Stearins~iure in Palmito-oleins~iure und Oleinsiiure iiberfiihrt wird. Key-words: Obese-hyperglycaemic mice, high-fat diet, d i e t a r y obesity, adipose tissue, liver, f a t t y acids. Introduction A h i g h - f a t diet a n d h e r e d i t a r y p r e d i s p o s i t i o n m a y l e a d to o b e s i t y b y v a r i o u s m e c h a n i s m s . D i e t a r y o b e s i t y is i n d u c e d u n d e r p r o p e r c o n d i t i o n s b e t w e e n w e i g h t increase to caloric i n t a k e ) , w i t h females a c c u m u l a t i n g m o r e f a t t h a n m a l e s [ 13, 14, 17, 18, 22 ]. The n u m b e r of f a t cells r e m a i n s n o r m a l in t h e e p i d i d y m a l f a t p a d s of r a t s [ 16 ]. E a c h f a t cell is h y p e r t r o p h i e d [ 16 ], b u t t h e levels of I%NA a n d T P N H b y a h i g h - f a t d i e t in r a t s a n d mice fed ad libitum. This g e n e r a t i n g e n z y m e s are low [ 7 ]. Lipogenesis is deprest y p e of o b e s i t y is a c c o m p a n i e d b y a n e l e v a t e d t h e r m o c h e m i c a l efficiency of g r o w t h (defined as t h e r a t i o sed in a d i p o s e tissue a n d l i v e r [ 4, 8, 12 ]. A d i p o s e tissue a n d muscle are i n s e n s i t i v e t o insulin in vitro [ 2, 21 ], and the rate of glucose utilization in vivo is depressed [ 4, 13 ]. The secretory activity of h-cells is low [ 1, 2, 21 ]. Hepatic glueoneogenesis from protein is probably stimulated b y a direct effect of the dietary f a t t y acids and b y a secondary hypercorticism [t5]. The autosomal recessive obesity of obese-hyperglycaeraie ( O - - H ) mice is quite different. This spontaneous obesity is due to the presence of ob gene in linkage group XI. The syndrome is characterized b y a high degree of hyperinsulinism [ 3 ]. The fat accumulated in 2-months-old O - - H mice maintained on a standard diet is poor in 18 : 2. ~ioreover, the glycerides stored b y adipose cells are rich in 1 6 : 1 and those present in the f a t t y liver contain an excess of 16 : 1 and 18 : 1 [ 26 ]. Two factors account for the quantitative and qualitative aspects of this endogenous obesity: 1. Lipogenesis is v e r y active and the c o n t r ~ u t i o n of the liver to adipose tissue glycerides is more import a n t in O - - I t mice t h a n in their lean littermates; 2. The enhanced activity of the particulate enzymes monodesaturating and elongating acyl-CoA is due to their induction b y insulin [ 26 ]. I t was thought of interest to see whether O - - H mice fed on a high-fat diet could be differentiated from O - - H mice maintained on a high-carbohydrate diet and from their lean littermates raised on the same diets. The purpose of this paper was to investigate whether obesity eonld be aggravated when hereditary and dietary factors were acting simultaneously, and also how the quality of the stored fat was influenced. Materials and Methods Ten obese-hyperglycaemic (ob/ob) male animals and 10 lean littermates (ob/ob+ or ob+/ob+) of the same sex were obtained from a colony of mice from the original stock V of Bar H a r b o r (Maine, U.S.A.) raised b y the Centre de S~lection e~ d'Elevage des animaux de laboratoire of the Centre National de la Recherche Scientifique (Orlgans -- La Source, France). These mice, previously maintained on a standard diet, were divided into 2 groups when 6 weeks old, each having the same mean body weight (42 g for O - - H mice and 28 g for control mice). Once distributed, the animals were fed ad libitum either a high-carbohydrate diet or a high-fat diet with the same protein content, until killing. The composition of the high.carbohydrate diet consisted of the following (in %, w/w): wheat flour, 78.3; casein, 12.1; DL-methionine, 0.4; salt mixture USP XIV, 4; bran, 3; vitamin mix, 2.2; the caloric source being 71% as carbohydrate, 7 % as fat and 22% as protein. The vitamin supplements in 100 g of diet were: thiamine 1.5 mg; riboflavin 1.5 mg; pyridoxine 1 mg; calcium pantothenate 5 mg; niacin 5 rag; vitamin B:~ 5 ~g; biotin 0.1 rag; choline chloride 200 mg; inositol 50 mg; p-aminobenzoic acid 30 rag; vitamin A 800 I . U . ; vitamin D a 200 I.U. ; vitamin E Diabetologia, YoI. 7 30 nag; menadione 1 rag; polyunsaturated f a t t y acids 280 mg. The low carbohydrate, high-fat diet was as follows : wheat flour, 7.6; casein, 30.0; salt mixture USP XIV, 6; lard, 41.5; bran, 4.5; vitamin mix, 3.3; the caloric source being 5 % as carbohydrate, 74% as fat and 22% as protein. As shown in Table 3, approximately 50% of the f a t t y acids present in the high-lard diet were saturated and the proportion of 18 : 2 was low (9%). The lipids accompanying the high-carbohydrate diet were rich in 18 : 2 (33%). After 4.5 months on these 2 diets (i.e. at the age of 6 months), all animals were killed b y decapitation between 10.30 A.M. and 12.30 P.M. The serum was collected b y centrifugation and stored at --30~ until analyzed for glucose with a glucose oxidase kit (Biotrol, Paris, France) and for i:sulin with the Sorin-Cea double antibody kit (Commissariat s l'Energie Atomique, Gif-sur-Yvette, France). The insulin immuneassays were conducted on sere adequately diluted ~dth 1% buffered bovine albumin. A rat insulin standard was a 5 crystalline preparation obtained through the courtesy of Dr. H. Ege (Nero Research Institute, Copenhagen, Denmark). The whole pancreas was carefully dissected, weighed and rapidly homogenized in acid-alcohol. After centrifugation, aliquots of the supernatants were diluted in 1% buffered bovine albumin for insulin assay [ 20 ]. Samples from the liver and the gastrocnemius of the hind leg were extracted in K O t t (30%, w/v) for assay of their glycogen [ 20 ]. Tl:ree pairs of fat pads were weighed: epididymaI, perirenal and subcutaneous (from the hip region). Fragments of the epididymal fat pads were fixed, embedded, sectioned, and examined as previously described [ 16, 17 ]. The lipids of adipose tissue and liver were studied on 6 animals. The pooled samples were extracted with chloroform-methanol (2:1). Liver lipids were fractionated b y thin-layer chromatography into neutral lipids and free f a ~ y acids, and into total phospholipids. The gas-chromatography of the f a t t y acid methylesters was conducted on Apiezon L as previously described [ 26 ]. The interrelations of f a t t y acids were estimated from their ~o distribution with the following four criteria. The mono-desaturation index of 1 6 : 0 was calculated as 1 6 : 1 / 1 6 : 0 + 1 6 : 1 , the naono-desaturation index of 18 : 0 as 18 : 1/18 : 0 + 18 : 1, the elongation index of 16 : 0 as 18 : 0 + 18 : 1/ 16 : 0 + 16 : 1 + 1 8 : 0 + 18 : 1, and the contribution of dietary lipids as 18 : 2/16 : 0. Results A. General parameters 1. Comparison of 6 months old O - - H mice fed on a high-carbohydrate diet with their lean littermates. 0bcse-hyperglycaemie mice were almost twice as h e a v y as lean littermates (Table 1). Subcutaneous and perirenal fat pads were 6- to 7-fold larger t h a n normal. The enlargment of epididymal fat pads was twofold and also significant ( p < 0 . 0 1 ) . The histological examination of sections of this perigenital fat reveals t h a t the number of adipose cells per fat p a d was not increased, b u t t h a t the size of these cells was about three times as large as t h a t in the nonobese (Table 2). There was no sign of fat cell degeneration. The proportion of mast cells present among fat cells was twice t h a t observed in the control fat pad. The weight of the liver was increased, although there was no liver h y p e r t r o p h y on a relative basis (Table 1). Liver glycogen was normal on a wet weight basis, b u t increased per organ. The glycogen content of the gastrocnemius was significantly elevated (p < 0.05) on a wet weight basis. Hypersecretion of the E-cells was characterized b y v e r y high levels of serum insulin (41 times the control value) and a normal insulin content of the pancreas (i.e. decreased stored insulin/ 100 g b o d y weight). The serum glucose was increased two-fold. 2. Effects of a high-fat diet on lean littermates and O - - H mice. The administration of a diet containing 41.5% lard for 4.5 months resulted in a moderate (-~ 11%) b u t significant increase of body weight in lean mice and was accompanied b y increased deposition in epididyreal and perirenal fat pads (Table 1). The slight hypert r o p h y of subcutaneous fat was not significant. In epididymal fat pads there was an h y p e r t r o p h y of adipose cells b u t no hyperplasia (Table 2). There is no apparent explanation for the significant elevation of serum insulin. In O - - H mice, the high-fat diet led to a spectacular 50% increase in body weight. I n these animals, it can be estimated, b y comparison with the weight of lean littermates, and knowing t h a t the fat-free b o d y weight is not increased [ 11 ], t h a t fat represented over 50% of the body weight. The increase in the weight of perirenal (-~211%) and subcutaneous fat pads (-~ 130%) was more important t h a n t h a t of epididy. mal fat (-~51%). A further enlargement of adipose cells was sufficient to account for the h y p e r t r o p h y of epididymal fat (Table 2). The liver did not participate in this increase in b o d y weight, and its contribution decreased therefore on a proportional basis (Table 1). Glycogen concentration was unaffected in the liver b u t depressed in the gastrocnemius b y the high-fat diet. Diabetes was not aggravated in spite of the reduction in the levels of serum insulin, and insulin stored in the pancreas. B. Comlgarison of fatty acid distribution in three fat pads of 6 months old O - - H mice, fed on a high-carbohydrate or a high-lard diet, with lcau littermates raised on the same diets. The f a t t y acid distribution of epididymal, subcutaneous and perirenal fat pads was comparable in each type of mice (i.e. was independant of their anatomical situation) (Table 3). T h a t adipose tissue obtained from different sites has similar f a t t y acid content has already been observed in rats [ 6 ] and men [ 10 ]. I n general, the fat stored in adipose cells of O - - I { mice on the high-carbohydrate diet, when compared with t h a t of lean littermates, showed a slight decrease in the relative contents of 16 : 0, 16 : 1 and 18 : 0, whereas 1 8 : 2 was normal and 1 8 : 1 elevated b y approximately 20% (Table 3). The four indices in Table 3 suggest t h a t these variations were mostly due to a 20% improvement in the elongation of 16 : 0. In lean mice on the high-fat diet, the proportions of 1 6 : 1 and 1 8 : 2 were halved and t h a t of 1 6 : 0 decreased b y 20%, whereas those of 18 : 0 and 18 : 1 showed a marked increase in the three fat pads (Table 3). The four indices (Table 3) indicate a reduction in the mono-desaturation of 16 : 0 and in the 18 : 2 content, and a better elongation of 1 6 : 0 (~-40%). I n O - - H mice, these qualitative variations were quite comparable with those observed in the lean littermates (Table 3). C. Comparison of fatty acid distribution in liver lipids of 6-month old O - - H mice fed on a high. carbohydrate or a high.lard diet with lean littermates raised on the same diets. In O - - H mice, neutral lipids (glycerides and free f a t t y acids) contained more 16 : 0 and less i8 : 2, w h e n compared with lean littermates (Table 4). The monodesaturation of 18 : 0 and the elongation of 16 : 0 were slightly elevated. There was v e r y little difference in total phospholipids between O - - I { mice and lean littermates, apart from a greater 18 : 0/18 : 1 ratio in obese animals. The high-fat diet had similar effects on the f a t t y acid distribution in the liver lipids of both groups of mice. I n neutral lipids, the 16 : 0/16 : 1 ratio increased and the proportion of 1 8 : 2 behaved similarly. In phospholipids, the mono-unsaturated f a t t y acids were decreased. The general composition of these lipids was reminiscent of the lard consumed, the only obvious difference being a better desaturation of 16 : 0 in the liver. Discussion A. Lean littermates on a high-fat diet The tendency towards obesity displayed on a highfat diet was less striking in Bar-i{arbor nonobese mice t h a n in Swiss albino mice and in rats on similar diets (Lemonnier, to be published, and ref. 13, 14, 17, 22). The variations in f a t t y acid distribution made the fat stored b y lean Bar-i{arbor mice somewhat similar to the lard consumed. However, the composition of the dietary fat was altered b y an increased elongation of f a t t y acids. This has also been observed in rats on a D. Lemonnier eta/. : Effects of a High-Fat Diet on Obese-Hyperglycaemic Mice high-fat diet [ 24 ]. The increased proportion of 18 : 2 observed in liver neutral lipids, in the face of a diet poor in 18 : 2, p r o b a b l y resulted from reduced hepatic lipogenesis. simultaneously. These results clearly confirm t h a t in general, obesity and h3Terinsulinism are not necessarily associated [ 21 ]. At the tissue level, it has already been demonstrated t h a t adipose tissue [ 5, 11, 19 ] and The age at killing corresponded p r o b a b l y to the period of m a x i m u m hyperinsulinism (Table 1 and ref. 25). The distribution of non-essential f a t t y acids obtained here in Paris, in the adipose tissues and liver glycerides of 6-months-old O - - t I mice, fed a highcarbohydrate diet, can be compared with the data previously obtained on 2-month-old O - - H animals fed a stock diet in B a r - H a r b o r [ 26 ]. The main difference appears to be a higher proportion of 1 8 : 1 in adult mice contrasting with an excess of 16 : 1 in the young animals previously studied. This shift a m o n g the mono-unsaturated f a t t y acids in O - - H mice could be due to ageing and/or to the diet. The elevated 1 8 : 2 / 1 6 : 0 ratio, compared with the same ratio in lean littermates, suggests a decreasing capacity of adipose tissue for lipogenesis in ageing mice. This would confirm the effect of age observed i n vitro [ 4, 5 ] and i n vivo [11], when labelled precursors are metabolized b y adipose tissue. On the other hand, the low 18 : 2/16 : 0 ratio in liver neutral lipids suggests t h a t a high lipogenetic activity was maintained in this organ, w h e n compared with 6-month old lean littermates. C. Obese-hyperglyeaemic mice maintained on a highf a t diet. Our results demonstrate a tremendous capacity in this hereditary syndrome to deposit fat without a n y control. The interaction of the high-fat diet and the ob/ob genotype exerted cumulative effects on the weight of the three fat pads examined, and on the size of fat cells in epididymal adipose tissue. Opposite effects on serum insulin and muscle glycogen were encountered when these two factors were acting muscle [ 23 ] are relatively unresponsive to dietary and hormonal manipulation in O - - H mice. The enlargement of adipose cells and an increased n u m b e r of m a s t cells, capable of releasing heparin (a known activator of lipoprotein lipase), might account for the increased weight of epididymal fat pads, without concurrent hyperplasia (Table 2, and ref. 9). The contribution of lipogenesis and dietary fat to the glycerides accumulated in O - - H mice can be estimated approximately from the comparison of the 18 : 2 content in adipose cells and in the diet. On the high-carbohydrate diet, the proportion of 18 : 2 in fat depot corresponded to 45% of the 18 : 2 content of the vegetable oil present in the diet (Table 3). The bodies of these mice p r o b a b l y contained as much as 42% f a t t y acids b y weight [ 4, 5, 11 ]. I t is therefore probable t h a t of the 27 g of f a t t y acids stored b y these 63 g mice, 12 g were of dietary origin and 15 g endogenous. When the same t y p e of mice was maintained on a high-fat diet, the 18 : 2 content of adipose fat was only 19% lower t h a n t h a t present in lard. This suggests t h a t lipogenesis was responsible for only 20% of total depot fat. The fat depot of these mice (with a b o d y weight of 94 g) amounting to 58 g [27 g + (94 g - - 63 g)], was therefore m a d e up of 4 times more exogenous f a t t y acids (47 g) t h a n endogenous f a t t y acids (11 g). The capacity of fat cells to accept dietary f a t t y acids was obviously v e r y high. Net lipogenesis was hardly inhibited (one g r a m less t h a n on the high carbohydrate diet), and still much higher t h a n the total a m o u n t of fat deposited in lean littermates submitted to the same diet (2.5 g, i.e. 6 % of a total b o d y weight of 41 g) [ 4 ]. The lack of depression of lipogenesis in O - - H mice b y dietary fat is in agreement with previous work i n vitro [ 19 ], but in contrast with data obtained in vivo, where a decreased incorporation of labelled glucose D. Lemonnier et al. : Effects of a I I i g h - F a t Diet on Obese-iiyperglycaemic Mice [ 26 ] is n o t l i m i t e d to t h e p r o d u c t s of lipogenesis a n d c a n be e x t e n d e d t o d i e t a r y f a t t y acids. Acknowledgements. This work was supported in p a r t b y the financial assistance of the Actions Concertdes of the I n s t i t u t N a t i o n a l de la Sant6 et de la l~echerche Mddicale (Paris, France) a n d b y contract 1105 of the F o n d s de la Recherche Seientifique Mddicale (Brussels, Belgium). The authors arc indebted to Mrs. Alexiu a n d MM. Suquet a n d I-Iebbelinck for their excellent technical assistance. 1. Best , C.II. , I-Iaist , R . E . , l~idout, J . t t . : Diet a n d insulin c o n t e n t of pancreas . J. Physiol. 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D. Lemonnier, J. Winand, J. Furnelle, J. Christophe. Effect of a high-fat diet on obese-hyperglycaemic and non-obese Bar Harbor mice, Diabetologia, 1971, 328-333, DOI: 10.1007/BF01219466