Development of obesity in transgenic mice after genetic ablation of brown adipose tissue

Abstract

Brown adipose tissue, because of its capacity for uncoupled mitochondrial respiration, has been implicated as an important site of facultative energy expenditure. This has led to speculation that this tissue normally functions to prevent obesity. Attempts to ablate or denervate brown adipose tissue surgically have been uninformative because it exists in diffuse depots and has substantial capacity for regeneration and hypertrophy. Here we have used a transgenic toxigene approach to create two lines of transgenic mice with primary deficiency of brown adipose tissue. At 16 days, both lines have decreased brown fat and obesity. In one line, brown fat subsequently regenerates and obesity resolves. In the other line, the deficiency persists and obesity, with its morbid complications, advances. Obesity develops in the absence of hyperphagia, indicating that brown fat deficient mice have increased metabolic efficiency. As obesity progresses, transgenic animals develop hyperphagia. This study supports a critical role for brown adipose tissue in the nutritional homeostasis of mice.

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

“…Further studies to measure the rates of beta-cell turnover will be required to find the relative contributions of these two processes to the beta-cell mass expansion of obese FVB mice. The syndrome of hyperinsulinaemic hyperglycaemia is probably a trait intrinsic to the genetic makeup of the FVB strain since manipulations of adipose-tissue mass, either by the A-ZIP-F1 dominant negative transcription factor [31] or by the BAT-specific toxigene, UCP-diphtheria toxin transgene [30], in FVB mice cause a similar diabetes phenotype of hyperinsulinaemic hyperglycaemia as produced by disruption of the leptin-leptin receptor system in the F-db mice.…”

“…Previous studies had indicated that most strains that carry either the ob or the db mutations have one of two major diabetes phenotypes: (i) transient hyperglycaemia followed by near euglycaemia and hyperinsulinaemia (exemplified by the C57BL/6J congenic strains) or (ii) persistent hyperglycaemia and early mortality due to loss of beta-cell mass (exemplified by the C57BLKS/J congenic strains). Some transgenic studies have indicated that FVB mice that become obese or are leptin deficient develop a syndrome of severe hyperglycaemia and extreme insulin resistance [30,31]. This suggested that it is possible to have prolonged hyperglycaemia and maintain hyperinsulinaemia.…”

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

“…WAT is directly innervated by the SNS, as has been established for BAT [16]. Mice lacking BAT due to the production of diphtheria toxin in this tissue are obese and insulin-resistant [17], indicating the importance of BAT in the control of body weight. Administration of β-adrenergic receptor (AR) agonists increases the metabolic rate [18][19][20], and mice lacking all three β-AR genes become markedly obese when reared on a HFD [21].…”

Genetics of human obesity: lessons from mouse models and candidate genes

“…Although comparatively little association was seen with obesity at the same loci, these data warrant a thorough analysis of this gene for possible functional gene variants. Recently, a third UCP-gene, UCP3, has been reported [114,115] which is even more abundantly expressed in muscle, and which, interestingly, is located only 10 kb downstream of UCP2 on chromosome 11, making this another plausible candidate for both mob-1/obq-1 and the loci controlling RMR. The ongoing studies on these genes may reveal new interesting gene variants associated with obesity.…”