Investigators: Abigail Haka, Ph.D.
Institution: Weill Cornell Medical College

Investigator's profile

Dr. Haka is interested in the use of optical spectroscopy and imaging techniques to elcuidate the role of macrophage lipid clearance in disease. In particular, her lab is interested to understand how macrophages catabolize objects that cannot be internalized by standard phagocytic mechanisms. Her lab has also studied another process called exophagy in the context of macrophage degradation of aggregated low density lipoproteins resulting in foam cell formation. A detailed understanding of these processes is essential for developing new strategies to prevent atherosclerosis.

Significance & Background

Macrophages catabolize objects that cannot be internalized by standard phagocytic mechanisms. This novel method of degradation affects the biology of conditions such as atherosclerosis and white adipose tissue inflammation (WATi). Similarly, exophagic catabolism of aggregated LDL results in uptake of cholesterol by the macrophage leading to foam cell formation, an integral part of atherosclerotic plaque formation. It is imperative to identify those subjects who harbor this chronic, low-grade inflammation prior to the development of disease. While WATi is common in the obese, it is recognized that as many as 30% of phenotypically obese individuals may be metabolically healthy [1,2], while significant metabolic abnormalities occur in others despite having a normal body mass index (BMI) [3]. Hence, precisely defining the population most likely to benefit from targeted intervention(s) to reverse WATi is a challenge and requires a more sophisticated assessment than BMI alone.

Approach

Sensitive spectroscopic characterization based on endogenous contrast mechanisms offers a powerful tool for non-invasive detection of WATi. Detection strategies currently under investigation, such as positron emission tomography (PET) and magnetic resonance imaging, require the administration of exogenous contrast agents, involve exposure to high-dose radiation, and have not been rigorously tested in humans [4]. To this end, leveraging the capabilities of the portable Raman spectroscopy system developed by the LBRC, the Haka laboratory has demonstrated the ability of sponateous Raman spectroscopy to detect WATi and shown its diagnostic ability in diverse tissue specimens both ex vivo (Fig. 1) and in vivo [12]. Figure 1 specifically shows WATi detection in epididymal fat from a mouse model of diet-induced obesity using Raman spectroscopy with perfect accuracy. Figure 1(A) shows the average body weights of mice on the low fat diet (LFD) (noninflamed) and high fat diet (HFD) (inflamed) at the time of sacrifice (n = 10/group). The asterisk (*) denotes p < 0.001. A crown like structure (CLS), as shown in Fig. 1(B), in the WAT from a mouse on the HFD stained with H&E can be seen. Figure 1(C) shows average number of CLS/cm² in mice on the LFD and HFD. The Raman spectra from inflamed (red, HFD) and noninflamed (blue, LFD) epididymal WAT are shown in Fig. 1(D). Clear differences in the spectra of inflamed and noninflamed WAT can be seen, particularly in the intensity of the Raman peaks at 1264 and 1652 cm^-1 (arrowed features). Diagnostic scatter plots based on the peak heights of the 1264 and 1652 cm^-1, which can separate inflamed (red) from noninflamed (blue) WAT with 100% accuracy are shown in Fig. 1(E). Prospective application on 10 mice also provide accurate identification of inflammatory tissue. The diagnoses are based primarily on changes in fatty acid saturation that occur in association with adipocyte hypertrophy, which is a known correlate of WATi.

Center offering

First, LBRC provides a fiber-probe based portable Raman spectroscopy unit that is ideal for WATi measurements both ex vivo and in vivo. Second, since these studies are performed in the absence of specific contrast agents, the acquired Raman signal presents a composite signature of numerous tissue constituents. Hence, transcutaneous measurements, in particular, necessitate the development of advanced chemometric models, which have been developed by the LBRC. Together, these offerings empower noninvasive data acquisition and WATi recognition in clinical settings that would represent a critical milestone in translation. Future studies will also evaluate the feasibility of this tool for assessing the efficacy of therapeutic interventions (behavioral, dietary, pharmacological) aimed at attenuating WATi and subsequent disease.

References

1. "Metabolically healthy obesity from childhood to adulthood - Does weight status alone matter?," Metabolism, 63(9), pp. 1084-92, Sep 2014. [ Pubmed ]
2. "Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue," Journal of Lipid Research, 53, 792-801, Feb 2012. [ Pubmed ]
3. "Lean people with dysglycemia have a worse metabolic profile than centrally obese people without dysglycemia," Diabetes Technology & Therapeutics, 16(2), pp. 91-6, Feb 2014. [ Pubmed ]
4. "Arterial and fat tissue inflammation are highly correlated: a prospective 18F-FDG PET/CT study," European journal of nuclear medicine and molecular imaging, 41(5), pp.934-45, May 2014. [ Pubmed ]