Lean Pups Research Articles

Brown fat thermogenesis and its role in the development of obesity

The role of brown fat thermogenesis in the development of obesity is considered from a number of perspectives. In adult rats, the impact of scapular brown fat lipectomy on carcass fat accretion was examined in three different rodent models: the Zucker lean (Fa/−) rat which is relatively resistant to obesity, the Zucker obese (fa/fa) rat which is characterized by a particularly severe form of hyperplastic obesity and the Osborne Mendel rat which remains lean on a standard pelleted diet but readily becomes obese on a palatable high fat diet. The consequences of brown fat lipectomy varied from no effect on carcass white fat accretion in Zucker Fa/− lean rats to a significant increase in adiposity in the Zucker fatty fa/fa relative to their respective sham-operated controls. The effect of the Osborne Mendel rat was intermediate between the Fa/− and the fa/fa. The results point to the importance of genetic background with respect to the impact of brown fat lipectomy on the development of white fat adiposity. In the developing Zucker rat at 2 and 8 days of age, in vivo evidence is presented to support the concept that brown fat thermogenesis is attenuated in the fatty fa/fa preobese pup. In animals of the fatty fa/fa genotype, maximum oxygen consumption in response to acute cold exposure was lower than in lean pups of the Fa/Fa genotype. Moreover, at 8 days of age, the rectal temperature of the cold-exposed fa/fa pups fell more precipitously than did that of the lean during the period of cold exposure. The genetic obesity of the fatty fa/fa rat at 8 days of age was contrasted with that of 8-day old Zucker genetically lean Fa/Fa pups raised in small litters, a manipulation that results in a type of dietary obesity. The rate of oxygen consumption in response to cold was significantly increased in the overfed pups as compared to both genetically obese (fa/fa) pups and genetically lean (Fa/Fa) pups raised in normal sized litters. Our data support the concept that although the obesity of the fatty fa/fa rat pup was associated with a failure of brown fat mediated thermogenesis, there appeared to be no such failure in the overfed Fa/Fa lean pups during the initial phase of overfeeding.

Involvement of the cholinergic system in insulin and glucagon oversecretion of genetic preobesity.

The etiology of the abnormal secretion of hormones from the endocrine pancreas of genetically obese (fa/fa) rats is unknown. In this study, we tested the postulate that there is an early occurrence of increased efferent parasympathetic activity to the endocrine pancreas of these rodents. Unweaned female 17-day-old pups were anesthetized and tested by an iv bolus of arginine to stimulate insulin and glucagon output. At the time of the tests, pups were indistinguishable from each other. They were, therefore, kept to adulthood to allow for their separation into an obese (25% of total animals) and a lean (75%) group. Those animals that became obese were retrospectively referred to as preobese. Basal insulinemia and glucagonemia were identical in the two groups, as were the dynamics of arginine-induced hormone release. However, arginine-induced insulin as well as glucagon output were higher in preobese than in lean pups. These two abnormalities were abolished by acute atropine pretreatment. It is concluded that the substrate-induced insulin and glucagon oversecretion of preobese pups is an early defect that is mediated via the vagus nerve.

Rôle du tissu adipeux brun dans le développement de l'obésité génétique du rat Zucker obèse (fa/fa)

The lipogenic capacity and thermogenic activity (assessed by GDP binding to mitochondrial) of brown adipose tissue was studied in lean (Fa/fa) and obese (fa/fa) suckling Zucker rat pups 2 and 10 days old. By 10 days of age, fat deposition, lipogenesis in vivo and fatty acid synthetase activity were 1.5 to 2-fold higher, whereas GDP binding to mitochondria was 40% lower in pre obese than in lean pups. Compared with lean pups, 2-day old fa/fa pups showed a 60% increase in triglyceride accumulation in interscapular brown adipose tissue and a 30% decrease in GDP binding to mitochondria, while no change occurred in fatty acid synthetase activity. These results strongly suggest that an impaired thermogenic activity in the brown adipose tissue of fa/fa pups could play a key role in the development of obesity. However, the concomitant increase in fat content in the brown adipose tissue of 2-day old pre-obese pups raises the question of the causal relationship between these two disorders.

Development of fatty acid-synthetic capacity in interscapular brown adipose tissue during suckling in genetically obese Zucker rats.

The development of the lipogenic capacity in brown adipose tissue was studied in suckling lean (Fa/fa) and obese (fa/fa) Zucker pups aged from 7 to 22 days. In both lean and obese pups, activities of the two key lipogenic enzymes, fatty acid synthetase and acetyl-CoA carboxylase, and of citrate cleavage enzyme rose from the early to the late suckling period. Compared with lean pups, 7-day-old fa/fa pups showed a 35% increase in fat accumulation in interscapular brown adipose tissue and a 25% increase in fatty acid synthetase activity. By 10 days of age, fat deposition, lipogenesis in vivo (assessed by the incorporation of 3H from 3H2O into fatty acids) and fatty acid synthetase activity were 1.5-2-fold higher in pre-obese than in lean pups. Compared with lean pups, the increased lipogenesis in vivo observed in brown adipose tissue of 10-day-old pre-obese pups could not entirely account for the difference in fat deposition observed in this tissue, suggesting that additional mechanisms are at play to explain the increased fat content of this tissue.

Development of hepatic and adipose tissue lipogenic enzymes and insulinemia during suckling and weaning on to a high-fat diet in Zucker rats

This study was designed to monitor the developmental changes in insulinemia and lipogenic enzyme activities in both inguinal adipose tissue and liver during suckling (7, 9, 14, and 17 days of age) and weaning (22 and 30 days of age) on to either a low-fat or a high-fat diet in lean (Fa/fa) and obese (fa/fa) rats. Tissues were removed through surgery and genotypes were retrospectively determined. During suckling, there was no difference in liver enzyme activities between the two groups. In contrast, adipose tissue fatty acid synthetase was increased by 50% and citrate cleavage enzyme and malic enzyme by 30% by 9 days of age. By 17 days of age, there was a threefold elevation in these enzyme activities and 6-phosphogluconic dehydrogenase and a twofold increase in glucose-6-phosphate dehydrogenase per inguinal fat pad in fa/fa versus Fa/fa. Consistent with these results, fat pad weight was increased by 20%, 50%, and 100% at 9, 14, and 17 days of age, respectively, in obese as compared to lean pups. However only by 17 days of age could a slight but significant increase in insulin level be detected in obese pups. Enlargement of inguinal fat pad accelerated after weaning on to a low-fat diet and still more after weaning on to a high-fat diet. Weaning on to a low-fat diet elicited an induction of hepatic lipogenic enzymes two or three times greater in fa/fa than in lean pups, while weaning on to a high-fat diet blunted the differences between genotypes. The lipogenic enzyme activities displayed per total inguinal fat were three to ten times greater in obese than in lean pups, regardless of the diet. However, adipose tissue lipogenic enzyme activities were much lower after weaning on to a high-fat than on to a low-fat diet in obese pups. The high-fat diet was as effective as the low-fat diet in triggering hyperinsulinemia in obese pups. The increased adipose tissue capacity for lipogenesis, starting during the suckling period, could play an important etiologic role in the development and maintenance of obesity in the Zucker rat.-Bazin, R., and M. Lavau. Development of hepatic and adipose tissue lipogenic enzymes and insulinemia during suckling and weaning on to a high-fat diet in Zucker rats.

Effect of High Fat Weanling Diets Containing Either Medium-Chain Triglycerides or Long-Chain Triglycerides on the Development of Obesity in the Zucker Rat

Zucker rats were early weaned onto either medium-chain (MCT) or long-chain triglycerides (LCT) to examine the effect on the development of obesity. Preobese and lean pups were weaned at 16 days to isocaloric, isonitrogenous liquid diets containing either 65% MCT or LCT (by calories) or to a “stocklike” (5.5% fat, 72.6% carbohydrate) control diet or were pair-fed stocklike diet to MCT-fed rats until day 45. MCT-feeding lowered body weight gain and fat pad weight in obese and lean rats compared to stocklike-fed controls. Additionally, fat cell size and lipoprotein lipase (LPL) activity and hepatic acetyl CoA carboxylase activity were reduced in obese MCT-fed rats compared to obese controls fed stocklike diet. Except for altered LPL activity the effects produced by MCT-feeding were attributable to its anorectic effect. However, all obese rats, including the MCT group, developed an obese body composition and were hyperinsulinemic. The developmental sequence leading to obesity may be derived from a fundamental cellular defect that results in metabolic alterations in different tissues at critical periods of development. Thus, effective treatment of this genetic obesity requires a better understanding of fa gene action.high fat diet hyperinsulinemia lipoprotein lipase body composition

Development of pancreatic and plasma insulin in prenatal and suckling Zucker rats.

Pancreatic and plasma insulin concentrations in preobese and lean Zucker rats were determined during three developmental periods: 1) gestation, 2) suckling, and 3) postweaning. Individual fetal samples were derived from two types of matings: 1) homozygous obese males (fafa) with heterozygous females (Fafa), and 2) homozygous lean males and females (FaFa). Suckling and postweaned pups from similar matings were partially pancreatectomized, tail bled, and identified retrospectively. In 21-day-old fetuses bearing the fa gene, plasma insulin concentration was elevated (P less than 0.001) and pancreatic concentration was slightly lower (P less than 0.05) compared to homozygous lean fetuses. Neither pancreatic nor plasma insulin concentration differed between preobese and lean pups during suckling, except that pancreatic concentration became elevated in preobese pups on postnatal day 20 (P less than 0.05). Plasma insulin concentration was elevated 24 h postweaning (P less than 0.01). These data support the hypothesis that the fa gene initiates metabolic changes during gestation that are modulated during suckling, but reappear at weaning. The data also establish that increased adipocyte size and lipoprotein lipase activity in 7- to 12-day-old preobese pups are not dependent on concomitant hyperinsulinemia.

Onset and development of hypertriglyceridemia in the Zucker rat ( [formula omitted

Triglyceridemia was studied in genetically obese Zucker rats ( fa fa ) and their lean littermates aged 1–8 wk. Hypertriglyceridemia was manifest in the obese from 2 wk onwards. Hepatic triacylglycerol secretion rate (TGSR) measured after administration of Triton WR-1339, was similar in obese and lean pups aged 2 wk. At 4 wk TGSR was twice as high in the obese as in the lean. Lipoprotein lipase (LPL) activity was abnormal in the tissues of obese animals, being either increased in white adipose tissue from 1 wk onwards or decreased in brown adipose tissue and cardiac and skeletal muscle from 2 wk onwards. The simultaneous appearance in the 2-wk-old obese of a decrease in LPL activity of the latter tissues, and hypertriglyceridemia strongly suggests a cause-effect relationship particularly since TGRS is normal. After weaning, LPL capacity of white adipose tissue in the obese, although considerably increased, was apparently not high enough to compensate for both an increased TGSR and a decreased LPL activity in other tissues.

Suckling: Developmental indicator of genetic obesity in mice

The Bar Harbor obese-hyperglycemic mouse (ob/ob) characteristically develops its obese phenotype during the postweaning period, when access to food is unrestricted and its behavioral phenotype of hyperphagia appears. In the present study suckling behavior (viz., nipple attachment latencies and total suckling time) of lean and preobese mouse pups, derived from matings of heterozygous lean patients, was measured in either fed or fasted conditions from 6 to 21 days postpartum on anesthetized dams. Twenty-hour milk deprivation selectively channeled pup activity into suckling for both preobese and lean mice, although, in general, preobese mice nipple-attached sooner and suckled longer than leans. In particular, fed preobese pups suckled longer than fed lean pups from 18 days on, providing a preweaning behavioral indicant of a genetic tendency to obesity when environmental constraints on overeating are minimized.