Below Thermoneutrality, Changes in Activity Do Not Drive Changes in Total Daily Energy Expenditure between Groups of Mice

Virtue, Sam; Even, Patrick C.; Vidal-Puig, António

doi:10.1016/j.cmet.2012.10.008

Cited by 69 publications

(70 citation statements)

References 12 publications

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“…Interestingly, the increased locomotor activity of RIIβ KO mice contributes little to their lean phenotype because the hyperlocomotor activity can be completely rescued by reexpression of RIIβ in the striatum, and the lean phenotype persists. Although we found this result surprising, it is consistent with previous observations that physical activity is not directly correlated to body fat content in mice (13), and that daily activity does not drive differences in EE between two groups of mice at room temperature (25).…”

Section: Discussionsupporting

confidence: 72%

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Zheng¹,

Yang²,

Sikorski³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Targeted disruption of RIIβ-protein kinase A (PKA) in mice leads to a lean phenotype, increased nocturnal locomotor activity, and activation of brown adipose tissue. Because RIIβ is abundantly expressed in both white and brown adipose tissue as well as the brain, the contribution of neuronal vs. peripheral PKA to these phenotypes was investigated. We used a Cre-Lox strategy to reexpress RIIβ in a tissue-specific manner in either adipocytes or neurons. Mice with adipocyte-specific RIIβ reexpression remained hyperactive and lean, but pan-neuronal RIIβ reexpression reversed both phenotypes. Selective RIIβ reexpression in all striatal medium spiny neurons with Darpp32-Cre corrected the hyperlocomotor phenotype, but the mice remained lean. Further analysis revealed that RIIβ reexpression in D2 dopamine receptor-expressing medium spiny neurons corrected the hyperlocomotor phenotype, which demonstrated that the lean phenotype in RIIβ-PKA-deficient mice does not develop because of increased locomotor activity. To identify the neurons responsible for the lean phenotype, we used specific Cre-driver mice to reexpress RIIβ in agouti-related peptide (AgRP)-, proopiomelanocortin (POMC)-, single-minded 1 (Sim1)-, or steroidogenic factor 1 (SF1)-expressing neurons in the hypothalamus, but observed no rescue of the lean phenotype. However, when RIIβ was reexpressed in multiple regions of the hypothalamus and striatum driven by Rip2-Cre, or specifically in GABAergic neurons driven by Vgat-ires-Cre, both the hyperactive and lean phenotypes were completely corrected. Bilateral injection of adeno-associated virus1 (AAV1)-Cre directly into the hypothalamus caused reexpression of RIIβ and partially reversed the lean phenotype. These data demonstrate that RIIβ-PKA deficiency in a subset of hypothalamic GABAergic neurons leads to the lean phenotype.mouse genetics | obesity | exercise | cAMP W e reported previously that mice lacking the protein kinase A (PKA) regulatory subunit RΙΙβ (RΙΙβ KO) exhibit a 50% reduction in white adipose tissue (WAT) and are resistant to dietinduced obesity (DIO) and diabetes (1, 2). These mice have an extended lifespan and show diminished age-related metabolic dysfunctions such as fatty liver and insulin resistance (3). Compared with their WT littermates, RIIβ KO mice have normal to slightly increased food intake, a twofold increase in nocturnal physical activity, and a basal metabolic rate (VO 2 consumption) that is higher than WT if calculated based on total body weight (4-6). RIIβ is highly expressed in the mouse CNS, brown adipose tissue (BAT), and WAT with limited expression elsewhere (1, 7-9). At the molecular level, RIIβ deficiency is accompanied by a compensatory increase in the PKA regulatory subunit RIα, which results in increased basal PKA activity and decreased total C subunit activity in brain, BAT, and WAT (1). These changes in PKA subunit composition may also alter PKA holoenzyme localization to specific signaling complexes because RIIβ has a much higher affinity for anchoring proteins (AKAPs)...

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Section: Discussionsupporting

confidence: 72%

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Zheng¹,

Yang²,

Sikorski³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, induction of fat storage in adipocytes of ␤Glud1 Ϫ/Ϫ mice under HFD diet was prevented, pointing to limited insulin signaling (37). This effect does not rule out other putative contributions, such as central effects or subtle changes in thermogenesis potentially masked by the inherent multifactorial balance of energy expenditure (33), although ␤Glud1 Ϫ/Ϫ mice on the chow diet did not exhibit changes in weight gain.…”

Section: Discussionmentioning

confidence: 83%

“…Metabolic efficiency represents the fraction of ingested calories that is stored as extra energy substrates, in contrast to the major part that is directly used for cellular function and heat production (33). Metabolic efficiency over the 20 weeks on HFD was reduced by 57% in ␤Glud1 Ϫ/Ϫ mice compared with control mice (0.69g/MJ versus 1.6g/MJ, respectively, p Ͻ 0.01; Fig.…”

Section: ␤Glud1 ϫ/ϫ Mice Are Resistant To Diet-induced Obesitytaking mentioning

confidence: 97%

“…This was not the case for the ␤Glud1 Ϫ/Ϫ mice on a standard chow diet (data not shown), suggesting that the increased activity was not intrinsic to the loss of ␤-cell GDH. Of note, under standard animal housing typically below thermoneutrality, activity is unlikely to explain differences in energy expenditure (33).…”

Section: ␤Glud1 ϫ/ϫ Mice Are Resistant To Diet-induced Obesitytaking mentioning

confidence: 99%

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The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

Vetterli¹,

Carobbio²,

Frigerio³

et al. 2016

Journal of Biological Chemistry

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Efficient energy storage in adipose tissues requires optimal function of the insulin-producing ␤-cell, whereas its dysfunction promotes diabetes. The associated paradox related to ␤-cell efficiency is that excessive accumulation of fat in adipose tissue predisposes for type 2 diabetes. Insulin exocytosis is regulated by intracellular metabolic signal transduction, with glutamate dehydrogenase playing a key role in the amplification of the secretory response. Here, we used mice with ␤-cell-selective glutamate dehydrogenase deletion (␤Glud1 ؊/؊ ), lacking an amplifying pathway of insulin secretion. As opposed to control mice, ␤Glud1 ؊/؊ animals fed a high calorie diet maintained glucose tolerance and did not develop diet-induced obesity. Islets of ␤Glud1 ؊/؊ mice did not increase their secretory response upon high calorie feeding, as did islets of control mice. Inhibited adipose tissue expansion observed in knock-out mice correlated with lower expression of genes responsible for adipogenesis. Rather than being efficiently stored, lipids were consumed at a higher rate in ␤Glud1 ؊/؊ mice compared with controls, in particular during food intake periods. These results show that reduced ␤-cell function prior to high calorie feeding prevented diet-induced obesity.

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“…During this hour, the mice may display different levels of physical activity, and the energy expenditure of this activity would necessarily be included in the average energy expenditure. However, as observed elsewhere and discussed in general (22,42,50), and as demonstrated by Virtue et al (55) specifically for physical activity, at subthermoneutral temperatures such extra energy for physical activity does not necessarily add to the total energy expenditure, as the heat production for thermoregulation would be correspondingly diminished. Therefore, we have used total energy expenditure data for the calculations.…”

Section: Calculations and Statisticsmentioning

confidence: 93%

No insulating effect of obesity

Fischer

Csikasz

Essen

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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The development of obesity may be aggravated if obesity itself insulates against heat loss and thus diminishes the amount of food burnt for body temperature control. This would be particularly important under normal laboratory conditions where mice experience a chronic cold stress (at Ϸ20°C). We used Scholander plots (energy expenditure plotted against ambient temperature) to examine the insulation (thermal conductance) of mice, defined as the inverse of the slope of the Scholander curve at subthermoneutral temperatures. We verified the method by demonstrating that shaved mice possessed only half the insulation of nonshaved mice. We examined a series of obesity models [mice fed high-fat diets and kept at different temperatures, classical diet-induced obese mice, ob/ob mice, and obesity-prone (C57BL/6) vs. obesityresistant (129S) mice]. We found that neither acclimation temperature nor any kind or degree of obesity affected the thermal insulation of the mice when analyzed at the whole mouse level or as energy expenditure per lean weight. Calculation per body weight erroneously implied increased insulation in obese mice. We conclude that, in contrast to what would be expected, obesity of any kind does not increase thermal insulation in mice, and therefore, it does not in itself aggravate the development of obesity. It may be discussed as to what degree of effect excess adipose tissue has on insulation in humans and especially whether significant metabolic effects are associated with insulation in humans. obesity; insulation; ob/ob DESPITE THE PRESENT INTEREST IN METABOLISM in connection with the global obesity epidemic, there is little knowledge concerning the extent to which obesity as such affects metabolism. There is widespread interest in issues such as the release of adipokines from adipose tissue depots, but many basic issues, such as the ability of adipose tissue to affect metabolism physically, have been little examined. One of these issues is the question of the ability of adipose tissue to function as a thermal insulation barrier, decreasing the heat loss from the organism and in this way decreasing the amount of energy needed to keep the organism warm, thereby increasing the amount of excess energy prone to storage in the form of (additional) fat.Whether an insulating effect of obesity exists is of significance both for humans and for animal models of obesity. However, with regard to experimental animals, the issue of insulation is of further interest. This is because most metabolic experiments are conducted with mice kept under conditions (standard laboratory conditions of Ϸ21°C) that are principally cold for the mouse (10,19,27,37,38,42,44) and thus where a high proportion of total metabolism (nearly half) is devoted to counteracting the resulting heat loss. This is a condition very different from that which is relevant for the metabolic physiology of most humans (living in a thermoneutral environment). Thus, under the current experimental conditions for mice, an insulating effect of increasing obesit...

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Below Thermoneutrality, Changes in Activity Do Not Drive Changes in Total Daily Energy Expenditure between Groups of Mice

Cited by 69 publications

References 12 publications

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

No insulating effect of obesity

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