G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche

Li, Ziru; Hardij, Julie; Evers, Simon S.; Hutch, Chelsea R.; Choi, Sarah M.; Shao, Yuchao; Learman, Brian S.; Lewis, Kenneth T.; Schill, Rebecca L.; Mori, Hiroyuki; Bagchi, Devika P.; Romanelli, Steven M.; Kim, Ki‐Suk; Bowers, Emily; Griffin, Cameron; Seeley, Randy J.; Singer, Kanakadurga; Sandoval, Darleen A.; Rosen, Clifford J.; MacDougald, Ormond A.

doi:10.1172/jci126173

Cited by 36 publications

(43 citation statements)

References 53 publications

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“…The effects of HFD on cortical bone geometry in male C57Bl/6J mice are less consistent. Similar to our results, several groups report no effect on cortical bone parameters, (13,14,16,54) but the study that reported increased trabecular cross-sectional area also found a 7% increase in cortical area in the diaphysis and a 21% increase in polar moment of inertia (pMOI) relative to CFD. (53) Similarly, a 60% fat diet from 4-23 weeks of age resulted in an 11% increase in both diaphyseal Ct.Th and Ct.Ar relative to CFD, (18) while a 60% fat diet from 6-18 weeks resulted in slightly expanded diaphyseal marrow area, lower Ct.Th, and similar pMOI relative to CFD.…”

Section: Discussionsupporting

confidence: 90%

High Fat Diet-Induced Obesity Negatively Affects Whole Bone Bending Strength but not Cortical Structure in the Femur

Hanne¹,

Aj²,

Jl³

et al. 2019

Preprint

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1Although body mass index is positively associated with bone mineral density, suggesting obesity 2 is protective against fracture, elderly obese individuals experience greater fracture risk at certain 3 sites than non-obese peers, suggesting bone structural or material changes contribute to fragility. 4 Diet-induced obesity rodent studies have reported detrimental changes to bone microstructure and 5 some apparent-level material properties, but tissue-level material changes are not well understood. 6 Because adipose tissue is highly vascularized, and bone remodeling depends critically on 7 functional vascular supply, concurrent effects on osteovascular perfusion and structure may 8 provide insight about obesity-related bone fragility. This study aimed to determine the effects of 9 obesity on both tissue-level bone properties and osteovascular properties that could negatively 10 impact bone strength. Five-week-old male C57Bl/6J mice were fed either high fat diet (HFD) or 11 control fat diet (CFD) for 17 weeks and received daily treadmill exercise or remained sedentary 12 for eight weeks at ages 14-22 weeks. HFD negatively affected femur bending strength, with 18% 13 lower yield load than CFD. Although HFD negatively altered cancellous microstructure in the 14 distal femur, with 32% lower bone volume fraction than CFD, it did not affect cortical bone 15 geometry in the femoral metaphysis or diaphysis. HFD caused increased carbonate substitution 16 but had no effect on other composition metrics or apparent-or tissue-level material properties in 17 the femoral diaphysis. Exercise did not affect bone strength or microstructure but increased 18 endosteal mineralizing surface in the tibial diaphysis, mineral crystallinity and mineral-to-matrix 19 ratio in the femur, and blood supply to the proximal tibial metaphysis. HFD did not affect blood 20 supply in the tibia or 2D osteovascular structure in the distal femoral metaphysis, indicating that 21 HFD negatively affects cancellous bone without affecting osteovasculature. This study reveals that HFD negatively affected cancellous microstructure without affecting osteovascular structure, and 23 whole-bone strength without altering cortical geometry or material properties. 24 25 Keywords: 26 obesity, high fat diet, bone strength, material properties, exercise 27 28Over half of adults worldwide are overweight or obese. (1) Higher bone mineral density (BMD), a 29 primary determinant of bone strength (2) that is associated with decreased fracture incidence in 30 elderly men and women, (3,4) is associated with increasing body mass index (BMI) in both obese 31 and non-obese individuals. (4-7) However, increasing BMI in obese women is not as strongly 32 correlated with increasing BMD and estimated material strength compared to non-obese 33 women. (7,8) A meta-analysis reported that, despite having higher BMD, elderly obese individuals 34 experience higher fracture incidence at particular sites compared to non-obese individuals -obese 35 postmenopausal women have a h...

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Section: Discussionsupporting

confidence: 90%

High Fat Diet-Induced Obesity Negatively Affects Whole Bone Bending Strength but not Cortical Structure in the Femur

Hanne¹,

Aj²,

Jl³

et al. 2019

Preprint

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Section: Intestinal-derived Fgf15 Partially Preserves Bone and Bone Mmentioning

confidence: 87%

“…Previous studies in our lab have shown that loss of bone and BMAT (bone marrow adipose tissue) following VSG is independent of body weight and diet (Li et al, 2019). In the current study, VSG caused a precipitous loss of trabecular and cortical bone loss in Consistent with our previous studies, both "regulated" bone marrow adipose tissue, BMAT (rBMAT) in proximal tibia and "constitutive" BMAT (cBMAT) in distal tibia were decreased by VSG (representative images Figure 2M, N) (Li et al, 2019;Scheller et al, 2015). Interestingly, loss of intestinal FGF15 caused a baseline reduction of rBMAT in proximal tibia ranging from growth plate (GP) to tibia/fibula junction (T/F J), with nearly complete depletion after VSG ( Figure 2M Next, we challenged mice with a mixed meal for the assessment of postprandial glucose excursion, insulin and GLP-1 response.…”

Section: Intestinal-derived Fgf15 Partially Preserves Bone and Bone Mmentioning

confidence: 87%

“…A second component of lean tissue loss in the FGF15 INT-KO VSG mice was due to reduced bone mass ( Figure 2). Bariatric procedures including VSG can result in bone loss beyond the normal response to reduced loading from weight loss, or calcium deficiency from diminished absorption (Gregory, 2017;Kim et al, 2015a;Li et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…We bred these mice to VilCreERT2 mice and administered tamoxifen (intraperitoneal, 3 doses/150 mg/kg) to VilCreERT2; Fgf15 flox/flox and controls (VilCreERT2 and Fgf15 flox/flox). We validated exon 2 excision within latter jejunal and ileal mucosa, where Vertical Sleeve Gastrectomy (VSG) in mice and rats: Mice were maintained on a 60% HFD for 8 weeks prior to undergoing Sham or VSG surgery, as described previously (Evers et al, 2019;Kim et al, 2019;Patel et al, 2018). Mice were fasted overnight prior to day of surgery.…”

Section: Animals and Dietmentioning

confidence: 99%

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Intestinal-derived FGF15 preserves muscle and bone mass following sleeve gastrectomy

Bozadjieva-Kramer

Shin

Shao

et al. 2020

Preprint

Self Cite

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Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive, but provide the most effective long-term metabolic improvements in obese and Type 2 diabetic patients. These powerful effects of manipulating the gastrointestinal tract point to an important role of gastrointestinal signals in regulating both energy balance and metabolism. To that end, we have used mouse models of VSG to identify key gut signals that mediate these beneficial effects. Preliminary data from our rodent model of VSG led us to hypothesize a potential role for the hormone Fibroblast-Growth Factor15/19 (mouse/human ortholog) which pharmacologically can regulate many aspects of energy homeostasis and glucose handling. FGF15 is expressed in ileal enterocytes of the small intestine and is released postprandially. Like many other gut hormones, postprandial plasma levels in humans and ileal FGF15 expression in mice increase after VSG. We generated intestinal-specific FGF15 knock out (VilCreERT2;Fgf15 f/f ) mice and controls, which were maintained on 60% high-fat diet. Interestingly, ablation of intestinal FGF15 in adult mice results in little change to body weight or glucose regulation when challenged with a high-fat diet. Unlike what we had predicted, intestinal-specific FGF15 knock out mice lost more weight after VSG and this was a result of increased lean tissue loss compared to control mice. Further, the loss of bone mineral density observed after VSG in control mice was increased in intestinal-specific FGF15 knock out mice. Finally the effect of VSG to reduce hepatic cholesterol was also absent in intestinal-specific FGF15 knock out mice. These data point to an important role for intestinal FGF15 to protect the organism from deleterious effects of rapid weight loss that occurs after VSG.

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Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations

Zhang,

Tian,

Majumdar

et al. 2024

Comprehensive Physiology

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Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic‐rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521‐5579, 2024.

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G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche

Cited by 36 publications

References 53 publications

High Fat Diet-Induced Obesity Negatively Affects Whole Bone Bending Strength but not Cortical Structure in the Femur

High Fat Diet-Induced Obesity Negatively Affects Whole Bone Bending Strength but not Cortical Structure in the Femur

Intestinal-derived FGF15 preserves muscle and bone mass following sleeve gastrectomy

Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations

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