Genetically lean mice result from targeted disruption of the RIIβ subunit of protein kinase A

Cummings, David E.; Brandon, Eugene P.; Planas, Josep V.; Motamed, Kouros; Idzerda, Rejean L.; McKnight, G. Stanley

doi:10.1038/382622a0

Cited by 384 publications

(319 citation statements)

References 26 publications

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“…28,29 Both the NPY-de®cient and normal mice (data from NPY a and NPY a7 mice were grouped because they were equivalent) consumed slightly fewer grams of this HFD when compared to the daily food intake of mice fed a normal diet containing 4% calories from crude fat (Figure 1), because the fatty diet is more energy dense (5.56 kcalag) than the normal diet (3.93 kcalag). Thus, the energy intake of the mice on the HFD was actually greater (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice

1998

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OBJECTIVE: The goal of this study was to ascertain whether neuropeptide Y (NPY) is required in mice for the development of obesity induced by a high-fat diet (HFD), chemical lesions of the hypothalamus caused by monosodium glutamate (MSG) or gold thioglucose (GTG), impaired brown adipose tissue (BAT) due to a diphtheria toxin transgene driven by the uncoupling protein 1 promoter (UCP-DTA) or the lethal yellow agouti mutation (A y ). BACKGROUND: The obesity syndrome of the leptin-de®cient (ob/ob) mouse can be partially reversed by the genetic removal of NPY. In the murine models of obesity examined in this study, the animals become obese despite increased serum leptin levels, indicating that they are resistant to the weight-limiting actions of leptin. The role of NPY in these obesity models with elevated leptin levels is unknown. EXPERIMENTAL DESIGN: Mice lacking NPY due to genetic disruption of the gene and wildtype littermates were made obese by allowing them access to a highly palatable HFD, by treatment with MSG, or GTG, or by inheriting the dominant UCP-DTA or A y alleles. Food consumption, body weight and dissectable fat pad weights were measured and compared to values obtained from non-obese littermates. RESULTS: In each model of obesity tested, NPY-de®cient mice achieved the same food intake, body weight and fat content as wildtype littermates. CONCLUSION: NPY is not necessary for the progressive development of obesity exhibited by multiple murine models with leptin resistance.

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Section: Resultsmentioning

confidence: 99%

Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice

1998

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“…Since females are basically more sensitive to diet-induced obesity than males (Rodriguez & Palou, 2004), the effect of UCP1 deficiency on body weight regulation might be more apparent in females. PKA activation via β3-AR in adipose tissues has a pivotal role in the regulation of cold-induced thermogenesis and lipolysis (Prusiner et al, 1968;Cummings et al, 1996;Lowell & Spiegelman, 2000). In the cold, the sympathetic nervous system is activated, which then stimulates vasoconstriction (to suppress heat loss) and heat production.…”

Section: Discussionmentioning

confidence: 99%

UCP1 deficiency increases susceptibility to diet‐induced obesity with age

et al. 2005

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SummaryLoss of nonshivering thermogenesis in mice by inactivation of the mitochondrial uncoupling protein gene ( Ucp1 -/-mice) causes increased sensitivity to cold and unexpected resistance to diet-induced obesity at a young age. To clarify the role of UCP1 in body weight regulation throughout life and influence of UCP1 deficiency on longevity, we longitudinally analyzed the phenotypes of Ucp1 -/-mice maintained in a room at 23 °°°° C. There was no difference in body weight and lifespan between genotypes under the standard chow diet condition, whereas the mutant mice developed obesity with age under the high-fat (HF) diet condition. Compared with Ucp1 +/+ mice, Ucp1 -/-mice showed increased expression of genes related to thermogenesis and fatty acid metabolism, such as β β β β 3-adrenergic receptor, in adipose tissues of the 3-month-old mutants; however, the augmented expression was reduced in Ucp1 +/+ mice in 11-month-old Ucp1 -/-mice fed the HF diet. Likewise, the increased levels of UCP3 and cAMPdependent protein kinase in the brown adipose tissue of Ucp1 -/-mice given the standard diet were decreased significantly in that of Ucp1 -/-mice fed the HF diet, which animals showed impaired norepinephrine-induced lipolysis in their adipose tissues. These results suggest profound attenuation of β β β β -adrenergic responsiveness and fatty acid utilization in Ucp1 -/-mice fed the HF diet, bringing them to late-onset obesity. Our findings provide evidence that UCP1 is neither essential for body weight regulation nor for longevity under conditions of standard diet and normal housing temperature, but deficiency increases susceptibility to obesity with age in combination with HF diet.

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“…ectopic uncoupling protein 1 expression in WAT induces obesity resistance in mice (34) ; mice lacking insulin receptor only in BAT become diabetic (35) ; murine strains prone to develop obesity and diabetes have less BAT than obesity-and diabetes-resistant mice (35,37) ; obese rats treated with b3-agonists control obesity and diabetes and develop BAT (38)(39)(40)(41) ; many different models of transgenic mice with a clear brown phenotype of adipose organ are lean and obesity resistant (42)(43)(44) ; human subjects with more brown phenotype of abdominal subcutaneous fat have less insulin resistance then those showing a reduced brown phenotype (45) ; brown fat genes are reduced in visceral depots of obese individuals (46) .…”

Section: The Reversible Transdifferentiation Phenomenonmentioning

confidence: 99%

Reversible physiological transdifferentiation in the adipose organ

Cinti

2009

Proc. Nutr. Soc.

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All mammals are provided with two distinct adipose cells, white and brown adipocytes. White adipocytes store lipids to provide fuel to the organism, allowing intervals between meals. Brown adipocytes use lipids to produce heat. Previous descriptions have implied their localization in distinct sites of the body; however, it has been demonstrated that they are present together in many depots, which has led to the new concept of the adipose organ. In order to explain their coexistence the hypothesis of reversible physiological transdifferentiation has been developed, i.e. they are contained together because they are able to convert, one into the other. In effect, if needed the brown component of the organ could increase at the expense of the white component and vice versa. This plasticity is important because the brown phenotype of the organ is associated with resistance to obesity and its related disorders. A new example of reversible physiological transdifferentiation of adipocytes is offered by the mammary gland during pregnancy, lactation and post-lactation stages. The gravidic hormonal stimulus seems to trigger a transdifferentiation of adipocytes into milk-producing and secreting epithelial glands. In the post-lactation period some of the epithelial cells of the mammary gland seem to transdifferentiate into adipocytes. Recent unpublished results suggest that explanted adipose tissue, as well as explanted isolated mature adipocytes, is able to transdifferentiate into glands with epithelial markers of milk-secreting mammary glands. These findings, if confirmed, seem to suggest new windows into the cell biology frontiers of adipocytes.

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Genetically lean mice result from targeted disruption of the RIIβ subunit of protein kinase A

Cited by 384 publications

References 26 publications

Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice

Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice

UCP1 deficiency increases susceptibility to diet‐induced obesity with age

Reversible physiological transdifferentiation in the adipose organ

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