Revisiting Lessons from the C57BL/6J Mouse

The following is an abstract of the article discussed in the subsequent letter:


    ABSTRACT

Watson, Patricia M., Scott P. Commins, Rudolph J. Beiler, Heather C. Hatcher, and Thomas W. Gettys. Differential regulation of leptin expression and function in A/J vs. C57BL/6J mice during diet-induced obesity. Am J Physiol Endocrinol Metab 279: E356-E365, 2000.---Obesity-resistant (A/J) and obesity-prone (C57BL/6J) mice were weaned onto low-fat (LF) or high-fat (HF) diets and studied after 2, 10, and 16 wk. Despite consuming the same amount of food, A/J mice on the HF diet deposited less carcass lipid and gained less weight than C57BL/6J mice over the course of the study. Leptin mRNA was increased in white adipose tissue (WAT) in both strains on the HF diet but to significantly higher levels in A/J compared with C57BL/6J mice. Uncoupling protein 1 (UCP1) and UCP2 mRNA were induced by the HF diet in brown adipose tissue (BAT) and WAT of A/J mice, respectively, but not in C57BL/6J mice. UCP1 mRNA was also significantly higher in retroperitoneal WAT of A/J compared with C57BL/6J mice. The ability of A/J mice to resist diet-induced obesity is associated with a strain-specific increase in leptin, UCP1, and UCP2 expression in adipose tissue. The findings indicate that the HF diet does not compromise leptin-dependent regulation of adipocyte gene expression in A/J mice and suggest that maintenance of leptin responsiveness confers resistance to diet-induced obesity.


    LETTER

Revisiting Lessons from the C57BL/6J Mouse

To the Editor: We were delighted to see the article by Watson et al. on "Differential regulation of leptin expression and function in A/J vs. C57BL/6J mice during diet-induced obesity" that was recently published in the American Journal of Physiology (AJP; Am J Physiol Endocrinol Metab 279: E356-E365, 2000). The work presents a comprehensive replication of work done in our laboratories over the past 12 years on these strains of mice (1-8). Replication of previously published results is always welcome, although it is rare that journals such as AJP devote such significant space to it. We were definitely pleased to see that Watson et al. were able to reproduce our findings so precisely, but we were somewhat surprised that much of what was presented in this paper seemed to ignore that almost all of these findings are already in the literature, some for over a decade. The finding that high-fat feeding differentially affects ob gene expression in A/J and B6 mice is novel. As the authors noted, this result is not surprising, because it has previously been reported that plasma leptin levels differ in A/J and B6 mice on high-fat diets (7), and there is ample evidence that levels of ob gene expression in adipose tissue are reflected in serum levels.


    REFERENCES

1.   Brownlow, BS, Petro AE, Feinglos MN, and Surwit RS. The role of motor activity in diet-induced obesity in C57BL/6J mice. Physiol Behav 69: 37-41, 1996.

2.   Collins, S, Daniel KW, Petro AE, and Surwit RS. Strain-specific response to beta 3AR agonist treatment of diet-induced obesity in mice. Endocrinology 138: 405-413, 1997[Abstract/Free Full Text].

3.   Collins, S, Kuhn C, Petro AE, Chrunyk B, Swick AG, and Surwit RS. Leptin and fat regulation. Nature 380: 677, 1996[ISI][Medline].

4.   Collins, S, and Surwit RS. Pharmacologic manipulation of ob expression in a dietary model of obesity. J Biol Chem 271: 9437-9440, 1996[Abstract/Free Full Text].

5.   Surwit, RS, Feinglos MN, Rodin J, Sutherland A, Petro AE, Opara EC, Huhn CM, and Rebuffe-Scrive M. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 44: 645-651, 1995[ISI][Medline].

6.   Surwit, RS, Kuhn CM, Cochrane C, McCubbin JA, and Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37: 1163-1167, 1988[Abstract].

7.   Surwit, RS, Petro AE, Parekh P, and Collins S. Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice. Diabetes 46: 1516-1520, 1997[Abstract].

8.   Surwit, RS, Wang S, Petro AE, Sanchis D, Raimbault S, Ricquier D, and Collins S. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci USA 95: 4061-4065, 1998[Abstract/Free Full Text].

9.   Watson, PM, Commins SP, Beiler RJ, Hatcher HC, and Gettys TW. Differential regulation of leptin expression and function in A/J vs. C57BL/6J mice during diet-induced obesity. Am J Physiol Endocrinol Metab 279: E356-E365, 2000[Abstract/Free Full Text].

Richard S. Surwit,
Sheila Collins,
Department of Psychiatry and Behavioral Sciences
Duke University Medical Center
Durham, NC 27710


    REPLY

To the Editor: The studies reported in our recent article (6) were motivated by the pioneering work of Drs. Surwit and Collins in the area of dietary obesity. In particular, we wanted to explore the mechanism underlying their recent observation that high-fat diets induce a short-lived but larger than predicted increase in serum leptin in obesity-resistant compared with obesity-prone mice (see Fig. 3D of Ref. 5). This involved replicating their experimental design, and at the behest of the referees, we provided basic observations about growth, fat deposition, food intake, and serum profiles to demonstrate that there was a common basis for comparing our findings with those published by the authors. We were particularly interested in the effect of high-fat diets on leptin expression, and found that leptin mRNA was significantly higher in obesity-resistant compared with obesity-prone mice at all time points during the study (Table 2 of Ref. 6). This differs from Surwit et al., who found that, after 6 wk on the high-fat diet, serum leptin in obesity-resistant mice was either similar to or lower than levels in obesity-prone mice. On the basis of our recent work showing that leptin inhibits its own expression through central modulation of sympathetic tone (1,2), we tested the hypothesis that differences in inhibitory regulation were responsible for diet-induced differences in leptin expression between the mouse strains. This was done by acutely treating mice of each strain with a selective beta 3-adrenergic receptor agonist after various times on the high-fat diet and evaluating the ability of the agonist to downregulate leptin mRNA. We found significant differences in the way leptin was regulated between the strains (Fig. 3 of Ref. 6) that were unrelated to any change in beta 3-adrenergic receptor expression or function in white adipose tissue. These findings are novel and likely related to observations from others showing that transcriptional regulation of gene expression by beta -agonists differs in adipocytes from A/J and C57BL/6J mice (3, 4). The challenge that lies ahead will be in defining the molecular basis for this difference and relating it to the relative propensity of mice from these two strains to become obese. The studies of Drs. Surwit and Collins have led the way in demonstrating the utility of this model system for studying diet-induced obesity and defining the role of the adipocyte in the process.


    REFERENCES

1.   Commins, SP, Marsh DJ, Thomas SA, Watson PM, Padgett MA, Palmiter RD, and Gettys TW. Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 140: 4772-4776, 1999[Abstract/Free Full Text].

2.   Commins, SP, Watson PM, Levin N, Beiler RJ, and Gettys TW. Central leptin regulates the UCP1 and ob genes in brown and white adipose tissue via different beta -adrenoceptor subtypes. J Biol Chem 275: 33059-33067, 2000[Abstract/Free Full Text].

3.   Guerra, C, Koza RA, Yamashita H, Walsh K, and Kozak LP. Emergence of brown adipocytes in white fat in mice is under genetic control---Effects on body weight and adiposity. J Clin Invest 102: 412-420, 1998[Abstract/Free Full Text].

4.  Koza RA, Hohmann SM, Guerra C, Rossmeisl M, and Kozak LP. Synergistic gene interactions control the induction of the mitochondrial uncoupling protein (UCP1) gene in white fat tissue. J Biol Chem 275: 34486-34492.

5.   Surwit, RS, Petro AE, Parekh P, and Collins S. Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice. Diabetes 46: 1516-1520, 1997[Abstract].

6.   Watson, PM, Commins SP, Beiler RJ, Hatcher HC, and Gettys TW. Differential regulation of leptin release and function in A/J versus C57BL/6J mice during diet-induced obesity. Am J Physiol Endocrinol Metab 279: E356-E365, 2000[Abstract/Free Full Text].

Thomas W. Gettys,
Departments of Medicine and Biochemistry and Molecular Biology
Medical University of South Carolina
Charleston, SC 29425


Am J Physiol Endocrinol Metab 280(5):E825-E826
0193-1849/01 $5.00 Copyright © 2001 the American Physiological Society