FGF21 Acts Centrally to Induce Sympathetic Nerve Activity, Energy Expenditure, and Weight Loss

Owen, Bryn M.; Ding, Xunshan; Morgan, Donald A.; Coate, Katie C.; Bookout, Angie L.; Rahmouni, Kamal; Kliewer, Steven A.; Mangelsdorf, David J.

doi:10.1016/j.cmet.2014.07.012

Cited by 439 publications

(474 citation statements)

References 45 publications

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“…BAT, which mediates adaptive nonshivering thermogenesis, seemed to be a likely candidate considering that it is dense with mitochondria and can undergo a substantial increase in energy expenditure upon stimulation (14). In addition, recent studies have established the sensitivity of BAT to stimulation through FGF21, which we also observed to be highly elevated in POLG mice fed a HFD (15,16). Because BAT functionality in POLG mice has not previously been described, we first explored the impact of diet by using a thermal infrared camera to quantify radiated heat from the scapular region.…”

Section: Resultssupporting

confidence: 62%

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Wall

Whyte

Suh

et al. 2015

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

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Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive response is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermogenesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long-known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress.

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Section: Resultssupporting

confidence: 62%

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Wall

Whyte

Suh

et al. 2015

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

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“…Given that CEACAM1 is not produced by adipose tissue (9), it is likely that adenoviral delivery of CEACAM1 drives the expression of a set of factors that mediate this positive effect on energy expenditure and adipose tissue biology (reversal of adipocytes' expansion and limited fibrosis and inflammation). One of these factors might be the rise in plasma FGF21 (47,48), which induces locomotor activity (49) to elevate energy dissipation (50,51). Recapitulating the protective effect of forced expression of hepatic WT CEACAM1 on metabolism (17) and on adipose tissue biology and energy expenditure (30) in response to HF diet, the restorative metabolic effect caused by hepatic adenoviral redelivery of WT CEACAM1 on adipocytes supports the critical role of hepatocytic CEACAM1 in regulating insulin action and metabolism in other tissues.…”

Section: Adenoviral-redelivery Of Ceacam1 Rescues Energy Expenditure mentioning

confidence: 81%

Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

Russo

Ghadieh

Ghanem

et al. 2016

Journal of Lipid Research

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Supplementary key words carcinoembryonic antigen-related cell adhesion molecule 1 • insulin resistance • nicotinic acid • lipolysis • insulin clearanceCirculating insulin levels, in part determined by hepatic insulin clearance, regulate insulin action (1-3). Insulin clearance, which occurs mostly in liver and to a lower extent in kidney, but not in skeletal muscle or white adipose tissue (WAT), plays a pivotal role in promoting insulin sensitivity (4). If impaired, it contributes to mounting hyperinsulinemia in obese humans (5, 6), thus constituting a risk factor for metabolic syndrome (7,8).Our studies on the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane glycoprotein that is highly expressed in liver and kidney, but not WAT or skeletal muscle (9), support these findings. Upon its phosphorylation by the insulin receptor, CEACAM1 promotes insulin clearance by upregulating receptor-mediated insulin uptake into clathrin-coated pits and degradation in hepatocytes (10). Moreover, it mediates a downregulatory effect on mouse fatty acid synthase Abstract Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance and mediating suppression of fatty acid synthase activity. Feeding C57BL/6J male mice with a high-fat (HF) diet for 3-4 weeks triggered a >60% decrease in hepatic CEACAM1 levels to subsequently impair insulin clearance and cause systemic insulin resistance and hepatic steatosis. This study aimed at investigating whether lipolysis drives reduction in hepatic CEACAM1 and whether this constitutes a key mechanism leading to diet-induced metabolic abnormalities. Blocking lipolysis with a daily intraperitoneal injection of nicotinic acid in the last two days of a 30-day HF feeding regimen demonstrated that white adipose tissue (WAT)-derived fatty acids repressed hepatic CEACAM1-dependent regulation of insulin and lipid metabolism in 3-month-old male C57BL/6J mice. Adenoviralmediated CEACAM1 redelivery countered the adverse metabolic effect of the HF diet on insulin resistance, hepatic steatosis, visceral obesity, and energy expenditure. It also reversed the effect of HF diet on inflammation and fibrosis in WAT and liver. This assigns a causative role for lipolysis-driven decrease in hepatic CEACAM1 level and its regulation of insulin and lipid metabolism in sustaining systemic insulin resistance, hepatic steatosis, and other abnormalities associated with excessive energy supply.-Russo, L., H. E. Ghadieh, S. S. Ghanem, Q. Y. Al-Share, Z. N. Smiley, C. Gatto-Weis, E. L. Esakov, M. F. McInerney, G. Heinrich, X. Tong, L. Yin, and S. M. Najjar. Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocytehepatocyte axis.

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“…In mice, FGF21 increases corticotropin-releasing hormone expression in hypothalamus, circulating glucocorticoid concentrations, and sympathetic outflow (18)(19)(20), which are linked to heightened anxiety. We, therefore, tested Klb fl/fl and Klb Camk2a mice in behavioral paradigms measuring anxiety, including novelty suppressed feeding (Fig.…”

Section: Resultsmentioning

confidence: 99%

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Schumann

Liu

O’Reilly

et al. 2016

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

225

223

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Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10 −12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

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FGF21 Acts Centrally to Induce Sympathetic Nerve Activity, Energy Expenditure, and Weight Loss

Cited by 439 publications

References 45 publications

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

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