Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans

Lee, Paul; Bova, Ron; Schofield, Lynne; Bryant, Wendy; Dieckmann, William J.; Slattery, Anthony; Govendir, Matt A.; Emmett, Louise; Greenfield, Jerry R.

doi:10.1016/j.cmet.2016.02.007

Cited by 155 publications

(121 citation statements)

References 27 publications

(27 reference statements)

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“…Changes in thermogenesis are known to affect metabolic responses in animals and humans 19, 46, 47 . Therefore, we next examined glucose tolerance in Ldlr −/− and Apoe −/− mice fed a cholesterol-enriched diet housed at 22°C and 30°C ambient temperatures.…”

Section: Resultsmentioning

confidence: 99%

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

Williams

Elvington

Ivanov

et al. 2017

Circulation Research

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Rationale Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective due to UCP1-dependent thermogenesis. Objective We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression. Methods and Results Using mouse models of atherosclerosis housed at three different ambient temperatures, we observed that cold temperature enhanced while thermoneutral housing temperature inhibited atherosclerotic plaque growth, as did deficiency in UCP1. However, while UCP1 deficiency promoted poor glucose tolerance, thermoneutral housing enhanced glucose tolerance, and this effect held even in the context of UCP1 deficiency. In conditions of thermoneutrality, but not UCP1 deficiency, circulating monocyte counts were reduced, likely accounting for fewer monocytes entering plaques. Reductions in circulating blood monocytes were also found in a large human cohort in correlation with environmental temperature. By contrast, reduced plaque growth in mice lacking UCP1 was linked to lower cholesterol. Through application of a positron emission tomography (PET) tracer to track CCR2+ cell localization and intravital 2-photon imaging of bone marrow, we associated thermoneutrality with an increased monocyte retention in bone marrow. Pharmacological activation of β3 adrenergic receptors applied to mice housed at thermoneutrality induced UCP1 in beige fat pads but failed to promote monocyte egress from the marrow. Conclusions Warm ambient temperature is, like UCP1 deficiency, atheroprotective, but the mechanisms of action differ. Thermoneutrality associates with reduced monocyte egress from the bone marrow in a UCP-1 dependent manner in mice and likewise may also suppress blood monocyte counts in man.

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Section: Resultsmentioning

confidence: 99%

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

Williams

Elvington

Ivanov

et al. 2017

Circulation Research

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“…2G). Since reduction in Pdx1 expression in pancreatic β-cells has been linked with an increased rate of apoptotic cell death [32, 33], possibly explaining the small islets, we then tested whether AAV-ΔFosB islets displayed a dysfunction in glucose-stimulated insulin secretion (GSIS). Surprisingly, despite smaller islet size and reduced Pdx-1 expression, the GSIS test performed on isolated AAV-ΔFosB pancreatic islets showed a dose-dependent increase in both basal insulin level and glucose-stimulated insulin secretion compared to control (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While the literature strongly supports the inverse relationship between SNS activation and glucose handling, an emerging body of work suggests that SNS innervation of brown fat (BAT) exerts a contrastingly positive effect on glucose handling and energy expenditure [15,31]. Recent studies have shown that BAT control of glucose utilization is orchestrated by SNS-sensitive uncoupling protein 1 (UCP1) and glucose transporter 4 (GLUT4) [32] and this activation is at least in part linked to the activity of hypothalamic AgRP neurons [33]. …”

Section: Discussionmentioning

confidence: 99%

Hypothalamic ΔFosB prevents age-related metabolic decline and functions via SNS

Sato

Idelevich

Nagano

et al. 2017

Aging

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The ventral hypothalamus (VHT) integrates several physiological cues to maintain glucose homeostasis and energy balance. Aging is associated with increased glucose intolerance but the underlying mechanisms responsible for age-related metabolic decline, including neuronal signaling in the VHT, remain elusive. We have shown that mice with VHT-targeted overexpression of ΔFosB, a splice variant of the AP1 transcription factor FosB, exhibit increased energy expenditure, leading to decreased adiposity. Here, we show that VHT-targeted overexpression of ΔFosB also improves glucose tolerance, increases insulin sensitivity in target organs and thereby suppresses insulin secretion. These effects are also observed by the overexpression of dominant negative JunD, demonstrating that they occur via AP1 antagonism within the VHT. Furthermore, the improved glucose tolerance and insulin sensitivity persisted in aged animals overexpressing ΔFosB in the VHT. These beneficial effects on glucose metabolism were abolished by peripheral sympathectomy and α-adrenergic, but not β-adrenergic, blockade. Taken together, our results show that antagonizing AP1 transcription activity in the VHT leads to a marked improvement in whole body glucose homeostasis via activation of the SNS, conferring protection against age-related impairment in glucose metabolism. These findings may open novel avenues for therapeutic intervention in diabetes and age-related glucose intolerance.

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“…[14][15][16] Considering the putative role of BAT in the control of insulin action, combined with the effect of ambient temperature on BAT activity, we hypothesized that the global increase in temperature contributes to the current type 2 diabetes epidemic. Recently, a positive association was found between outdoor temperature and glycated hemoglobin (HbA1c), 17 indicating that systemic glucose homeostasis is influenced by environmental temperature. However, the importance of this association, especially in relation to the increasing diabetes burden, has never been studied on the population level.…”

Section: Significance Of This Studymentioning

confidence: 99%

Diabetes incidence and glucose intolerance prevalence increase with higher outdoor temperature

Blauw

Aziz

Tannemaat

et al. 2017

BMJ Open Diab Res Care

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ObjectiveRising global temperatures might contribute to the current worldwide diabetes epidemic, as higher ambient temperature can negatively impact glucose metabolism via a reduction in brown adipose tissue activity. Therefore, we examined the association between outdoor temperature and diabetes incidence in the USA as well as the prevalence of glucose intolerance worldwide.Research design and methodsUsing meta-regression, we determined the association between mean annual temperature and diabetes incidence during 1996–2009 for each US state separately. Subsequently, results were pooled in a meta-analysis. On a global scale, we performed a meta-regression analysis to assess the association between mean annual temperature and the prevalence of glucose intolerance.ResultsWe demonstrated that, on average, per 1°C increase in temperature, age-adjusted diabetes incidence increased with 0.314 (95% CI 0.194 to 0.434) per 1000. Similarly, the worldwide prevalence of glucose intolerance increased by 0.170% (95% CI 0.107% to 0.234%) per 1°C rise in temperature. These associations persisted after adjustment for obesity.ConclusionsOur findings indicate that the diabetes incidence rate in the USA and prevalence of glucose intolerance worldwide increase with higher outdoor temperature.

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Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans

Cited by 155 publications

References 27 publications

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

Hypothalamic ΔFosB prevents age-related metabolic decline and functions via SNS

Diabetes incidence and glucose intolerance prevalence increase with higher outdoor temperature

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