Obesity and type 2 diabetes are associated with disturbances in insulin-regulated glucose and lipid fluxes and severe comorbidities including cardiovascular disease and steatohepatitis. Whole body metabolism is regulated by lipid-storing white adipocytes as well as "brown" and "brite/beige" adipocytes that express thermogenic uncoupling protein 1 (UCP1) and secrete factors favorable to metabolic health. Implantation of brown fat into obese mice improves glucose tolerance, but translation to humans has been stymied by low abundance of primary human beige adipocytes. Here we apply methods to greatly expand human adipocyte progenitors from small samples of human subcutaneous adipose tissue and then disrupt the thermogenic suppressor gene NRIP1 by CRISPR. Ribonucleoprotein consisting of Cas9 and sgRNA delivered ex vivo are fully degraded by the human cells following high efficiency NRIP1 depletion without detectable off-target editing. Implantation of such CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreases adiposity and liver triglycerides while enhancing glucose tolerance compared to implantation with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic enhancement of human adipocytes without exposing the recipient to immunogenic Cas9 or delivery vectors.
- MeSH
- bílé tukové buňky metabolismus MeSH
- buněčná diferenciace MeSH
- buněčné kultury metody MeSH
- CRISPR-Cas systémy genetika MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- dospělé kmenové buňky fyziologie MeSH
- editace genu metody MeSH
- guide RNA, Kinetoplastida genetika MeSH
- hnědé tukové buňky metabolismus transplantace MeSH
- lidé MeSH
- metabolismus lipidů genetika MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nuclear receptor interacting protein 1 genetika metabolismus MeSH
- obezita komplikace metabolismus terapie MeSH
- podkožní tuk cytologie MeSH
- porucha glukózové tolerance etiologie metabolismus terapie MeSH
- termogeneze genetika MeSH
- ztučnělá játra etiologie metabolismus prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.
BACKGROUND: The diminished glucose lowering effect of insulin in obesity, called "insulin resistance," is associated with glucose intolerance, type 2 diabetes, and other serious maladies. Many publications on this topic have suggested numerous hypotheses on the molecular and cellular disruptions that contribute to the syndrome. However, significant uncertainty remains on the mechanisms of its initiation and long-term maintenance. SCOPE OF REVIEW: To simplify insulin resistance analysis, this review focuses on the unifying concept that adipose tissue is a central regulator of systemic glucose homeostasis by controlling liver and skeletal muscle metabolism. Key aspects of adipose function related to insulin resistance reviewed are: 1) the modes by which specific adipose tissues control hepatic glucose output and systemic glucose disposal, 2) recently acquired understanding of the underlying mechanisms of these modes of regulation, and 3) the steps in these pathways adversely affected by obesity that cause insulin resistance. MAJOR CONCLUSIONS: Adipocyte heterogeneity is required to mediate the multiple pathways that control systemic glucose tolerance. White adipocytes specialize in sequestering triglycerides away from the liver, muscle, and other tissues to limit toxicity. In contrast, brown/beige adipocytes are very active in directly taking up glucose in response to β adrenergic signaling and insulin and enhancing energy expenditure. Nonetheless, white, beige, and brown adipocytes all share the common feature of secreting factors and possibly exosomes that act on distant tissues to control glucose homeostasis. Obesity exerts deleterious effects on each of these adipocyte functions to cause insulin resistance.
- MeSH
- béžové tukové buňky metabolismus MeSH
- bílé tukové buňky metabolismus MeSH
- hnědé tukové buňky metabolismus MeSH
- inzulinová rezistence fyziologie MeSH
- lidé MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
OBJECTIVE: Crosstalk between adipocytes and local neurons may be an important regulatory mechanism to control energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) expands sympathetic neurons within white adipose tissue (WAT) and stimulates the appearance of "beige" adipocytes. Here we tested whether WAT DNL activity can also influence neuronal regulation and thermogenesis in brown adipose tissue (BAT). METHODS AND RESULTS: Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. This increased sympathetic innervation could be observed at both 22 °C and 30 °C, indicating it is not a response to heat loss but rather adipocyte signaling. In contrast, selective ablation of FASN in brown adipocytes of mice (iUCP1FASNKO) failed to modulate sympathetic innervation and the thermogenic program in BAT. Surprisingly, DNL in brown adipocytes was also dispensable in maintaining euthermia when UCP1FASNKO mice were cold-exposed. CONCLUSION: These results indicate that DNL in white adipocytes influences long distance signaling to BAT, which can modify BAT sympathetic innervation and expression of genes involved in thermogenesis.
- MeSH
- adipozita MeSH
- béžové tukové buňky metabolismus MeSH
- bílá tuková tkáň metabolismus MeSH
- bílé tukové buňky metabolismus MeSH
- hnědá tuková tkáň metabolismus MeSH
- hnědé tukové buňky metabolismus MeSH
- lipogeneze MeSH
- myši MeSH
- neurony metabolismus MeSH
- obezita metabolismus MeSH
- signální transdukce MeSH
- syntázy mastných kyselin MeSH
- synthasa mastných kyselin, typ I genetika metabolismus MeSH
- termogeneze MeSH
- termoregulace MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Statin use is associated with increased calorie intake and consequent weight gain. It is speculated that statin-dependent improvements in lipid profile may undermine the perceived need to follow lipid-lowering and other dietary recommendations leading consequently to increased calorie intake. However, increases in calorie intake in statin users may also be related to statin-dependent decreases in satiety factors such as leptin, an adipocyte-derived adipokine. The objective of our study was to examine the direct effects of statins on leptin expression. Adipocytes are the main source of circulating leptin. Therefore, we examined the effects of atorvastatin and simvastatin on leptin expression in cultured human white adipocytes. We show that treatment of white adipocytes with simvastatin and atorvastatin decreases leptin mRNA expression (simvastatin: P = 0.008, atorvastatin: P = 0.03) and leptin secretion (simvastatin: P = 0.0001, atorvastatin: P = 0.0001). Both simvastatin and atorvastatin mediate decreases in leptin expression via extracellular-signal-regulated kinases 1/2 and peroxisome proliferator-activated receptor gamma pathways (simvastatin: P = 0.01, atorvastatin: P = 0.026). Additionally, statin treatment also induced expected increases in adiponectin, while decreasing monocyte chemoattractant protein 1 (MCP1) mRNA. Furthermore, statins increased secretion of both total as well as high molecular weight adiponectin while decreasing MCP1 secretion. To conclude, statins act directly on human white adipocytes to regulate adipokine secretion and decrease leptin expression. Leptin is an important satiety factor. Hence, statin-dependent decreases in leptin may contribute, at least in part, to increases in food intake in statin users.
- MeSH
- adiponektin biosyntéza MeSH
- atorvastatin škodlivé účinky MeSH
- bílé tukové buňky účinky léků metabolismus MeSH
- kultivované buňky MeSH
- leptin biosyntéza MeSH
- lidé MeSH
- simvastatin škodlivé účinky MeSH
- statiny škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.
- MeSH
- bílá tuková tkáň účinky léků metabolismus MeSH
- bílé tukové buňky účinky léků metabolismus MeSH
- kachexie etiologie metabolismus MeSH
- kultivované buňky MeSH
- lipogeneze účinky léků MeSH
- lipolýza účinky léků MeSH
- metabolismus lipidů účinky léků MeSH
- myši MeSH
- nádory komplikace metabolismus MeSH
- peptidové fragmenty farmakologie MeSH
- proteinkinasy aktivované AMP metabolismus farmakologie MeSH
- proteiny regulující apoptózu účinky léků metabolismus MeSH
- techniky in vitro MeSH
- termogeneze účinky léků MeSH
- uncoupling protein 1 účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- bílé tukové buňky fyziologie metabolismus MeSH
- genetické markery MeSH
- hnědá tuková tkáň fyziologie MeSH
- hnědé tukové buňky fyziologie metabolismus MeSH
- lidé MeSH
- nízká teplota MeSH
- obezita metabolismus patofyziologie MeSH
- termogeneze fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- Klíčová slova
- BAIBA,
- MeSH
- bílá tuková tkáň metabolismus MeSH
- bílé tukové buňky * metabolismus MeSH
- cvičení MeSH
- genetická transkripce účinky léků MeSH
- hnědá tuková tkáň metabolismus MeSH
- hnědé tukové buňky * metabolismus MeSH
- játra metabolismus účinky léků MeSH
- kyseliny aminoisomáselné * farmakologie krev MeSH
- lidé MeSH
- metabolické nemoci metabolismus MeSH
- obezita * metabolismus MeSH
- Check Tag
- lidé MeSH
