bims-mimbat 2024-11-17 papers

Nature. 2024 Nov 13.

NK2R control of energy expenditure and feeding to treat metabolic diseases.

The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes1. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects2-4, and so far, no safe energy-expending option has reached the clinic. Here we show that activation of neurokinin 2 receptor (NK2R) is sufficient to suppress appetite centrally and increase energy expenditure peripherally. We focused on NK2R after revealing its genetic links to obesity and glucose control. However, therapeutically exploiting NK2R signalling has previously been unattainable because its endogenous ligand, neurokinin A, is short-lived and lacks receptor specificity5,6. Therefore, we developed selective, long-acting NK2R agonists with potential for once-weekly administration in humans. In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signalling. Additionally, a hyperinsulinaemic-euglycaemic clamp reveals that NK2R agonism acutely enhances insulin sensitization. In diabetic, obese macaques, NK2R activation significantly decreases body weight, blood glucose, triglycerides and cholesterol, and ameliorates insulin resistance. These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programmes to improve energy homeostasis and reverse cardiometabolic dysfunction across species.

DOI: https://doi.org/10.1038/s41586-024-08207-0

Nat Commun. 2024 Nov 12. 15(1): 9585

Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression.

Shota Okagawa, Masaji Sakaguchi, Yuma Okubo, Yuri Takekuma, Motoyuki Igata, Tatsuya Kondo, Naoki Takeda, Kimi Araki, Bruna Brasil Brandao, Wei-Jun Qian, Yu-Hua Tseng, Rohit N Kulkarni, Naoto Kubota, C Ronald Kahn, Eiichi Araki.

Lipodystrophy and obesity are associated with insulin resistance and metabolic syndrome accompanied by fat tissue dysregulation. Here, we show that serine protease inhibitor A1 (SerpinA1) expression in the liver is increased during recovery from lipodystrophy caused by the adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces the proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to increased energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. SerpinA1 forms a complex with the Eph receptor B2 and regulates its downstream signaling in adipocytes. These results demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes.

DOI: https://doi.org/10.1038/s41467-024-53835-9

Nat Commun. 2024 Nov 07. 15(1): 9652

Preoperative methionine restriction induces perivascular adipose tissue browning and improves vein graft remodeling in male mice.

Peter Kip, Thijs J Sluiter, Michael R MacArthur, Ming Tao, Nicky Kruit, Sarah J Mitchell, Jonathan Jung, Sander Kooijman, Josh Gorham, Jonathan G Seidman, Paul H A Quax, Julius L Decano, Masanori Aikawa, C Keith Ozaki, James R Mitchell, Margreet R de Vries.

Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application to improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and pathologic vascular remodeling following vein graft surgery in male mice. RNA sequencing reveals that MetR enhances browning in arterial (thoracic aorta) perivascular adipose tissue (PVAT) and induces it in venous (caval vein) PVAT. Specifically, Ppara is highly upregulated in PVAT-adipocytes upon MetR. Furthermore, MetR dampens the postoperative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro. This study shows that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in MetR-induced browning of PVAT. Furthermore, we demonstrate the potential of short-term preoperative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

DOI: https://doi.org/10.1038/s41467-024-53844-8

J Biol Chem. 2024 Nov 05. pii: S0021-9258(24)02474-8. [Epub ahead of print] 107972

Acute inflammation upregulates FAHFAs in adipose tissue and in co-cultured adipocytes.

Meric Erikci Ertunc, Srihari Konduri, Zhichen Ma, Antonio F M Pinto, Cynthia J Donaldson, Jeremiah Momper, Dionicio Siegel, Alan Saghatelian.

Since the discovery of fatty acid hydroxy fatty acids (FAHFAs), significant progress has been made in understanding their regulation, biochemistry, and physiological activities. Here, we contribute to this understanding by revealing that inflammation induces the production of fatty acid hydroxy stearic acids (FAHSAs) and fatty acid hydroxyoctadecadienoic acids (FAHODEs) in white adipose tissue depots and in adipocytes co-cultured with macrophages. In LPS-induced co-culture systems, we confirm that adipose triglyceride lipase (ATGL) is required for inflammation-induced FAHFA generation and demonstrate that inflammation is necessary for producing hydroxy fatty acids. Chemically synthesized FAHODEs show anti-inflammatory activities in vivo, but only at supraphysiological concentrations. While endogenous FAHFAs are unlikely to be anti-inflammatory due to their low concentrations, conversion of pro-inflammatory hydroxy fatty acids into FAHFAs may modulate inflammation. We test this concept by showing the pro-inflammatory lipids-hydroxyeicosatetraenoic acids (HETEs) and leukotriene B4 (LTB4)-are converted into FAHFAs in cell culture, and that two LTB4-derived FAHFAs have are modestly anti- not pro-inflammatory. Further research is needed to establish whether these increased FAFHA levels have a role in inflammation or are simply markers of inflammation, but the discovery of significant increases in FAHFA upon acute inflammation advances our knowledge of FAHFAs.

Keywords: ATGL; FAHFA; HETE; HODE; LPS; LTB4; adipose tissue; inflammation; lipid

DOI: https://doi.org/10.1016/j.jbc.2024.107972

Trends Endocrinol Metab. 2024 Nov 07. pii: S1043-2760(24)00272-8. [Epub ahead of print]

Adipose tissue-gut microbiome crosstalk in inflammation and thermogenesis.

Erin E Mauney, Marsha C Wibowo, Yu-Hua Tseng, Aleksandar D Kostic.

Previously characterized as inert fat depots, adipocytes are now recognized as dynamic mediators of inflammatory tone, metabolic health, and nutrient homeostasis. As endocrine organs, specialized depots of adipose tissue engage in crosstalk between the gut, liver, pancreas, and brain to coordinate appetite, thermogenesis, and ultimately body weight. These functions are tightly linked to the inflammatory status of adipose tissue, which is in turn influenced by the health of the gut microbiome. Here, we review recent findings linking specific gut microbes and their secreted factors, including recently identified elements such as bacterial extracellular vesicles, to the functional status of adipocytes. We conclude that further study may generate novel approaches for treating obesity and metabolic disease.

Keywords: adipose tissue; inflammation; microbiome; thermogenesis

DOI: https://doi.org/10.1016/j.tem.2024.10.004

Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2409509121

The Warburg Effect is the result of faster ATP production by glycolysis than respiration.

Matthew A Kukurugya, Saharon Rosset, Denis V Titov.

Many prokaryotic and eukaryotic cells metabolize glucose to organism-specific by-products instead of fully oxidizing it to carbon dioxide and water-a phenomenon referred to as the Warburg Effect. The benefit to a cell is not fully understood, given that partial metabolism of glucose yields an order of magnitude less adenosine triphosphate (ATP) per molecule of glucose than complete oxidation. Here, we test a previously formulated hypothesis that the benefit of the Warburg Effect is to increase ATP production rate by switching from high-yielding respiration to faster glycolysis when excess glucose is available and respiration rate becomes limited by proteome occupancy. We show that glycolysis produces ATP faster per gram of pathway protein than respiration in Escherichia coli, Saccharomyces cerevisiae, and mammalian cells. We then develop a simple mathematical model of energy metabolism that uses five experimentally estimated parameters and show that this model can accurately predict absolute rates of glycolysis and respiration in all three organisms under diverse conditions, providing strong support for the validity of the ATP production rate maximization hypothesis. In addition, our measurements show that mammalian respiration produces ATP up to 10-fold slower than respiration in E. coli or S. cerevisiae, suggesting that the ATP production rate per gram of pathway protein is a highly evolvable trait that is heavily optimized in microbes. We also find that E. coli respiration is faster than fermentation, explaining the observation that E. coli, unlike S. cerevisiae or mammalian cells, never switch to pure fermentation in the presence of oxygen.

Keywords: Warburg Effect; cancer metabolism; energy metabolism; modeling; systems biology

DOI: https://doi.org/10.1073/pnas.2409509121